Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	ACCEPT	Summary: CREB1 is a well-established bZIP transcription factor that binds DNA as dimers and activates RNA polymerase II-dependent transcription. This is a core molecular function supported by extensive literature including structural studies of the bZIP domain and functional studies of CRE-dependent transcription (Belgacem & Borodinsky 2017, Steven et al. 2020). Reason: Core molecular function. CREB1 contains a bZIP domain (IPR004827) and KID domain (IPR003102) characteristic of this transcription factor family. IBA annotation is well-supported by phylogenetic conservation across eukaryotes. Supporting Evidence: PMID:1655749 ATF-1, like CREB, is expressed in a wide variety of cell types, and ATF-1 is capable of dimerizing with CREB. Both ATF-1 homodimers and ATF-1/CREB heterodimers bind to the CRE file:human/CREB1/CREB1-deep-research-falcon.md model: Edison Scientific Literature
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: CREB1 regulates transcription by RNA polymerase II through binding to CRE elements and recruiting coactivators. This is a core biological process annotation directly related to its molecular function as a transcription factor. Reason: Core biological process. CREB1 directly regulates Pol II-dependent transcription by binding CRE sites and recruiting CBP/p300 coactivators upon phosphorylation. Supporting Evidence: PMID:11522779 transcription of a PEPCK chloramphenicol acetyltransferase (CAT) reporter gene activated by protein kinase A (PKA) is enhanced 7-fold by SRCAP
GO:0141156 cAMP/PKA signal transduction	IBA GO_REF:0000033	ACCEPT	Summary: CREB1 is a central effector of cAMP/PKA signaling. PKA phosphorylates CREB1 at Ser-119, enabling recruitment of CBP/p300 and transcriptional activation of cAMP-responsive genes. This is a defining feature of CREB1 function. Reason: Core function - CREB1 is literally named for its role as a cAMP-responsive element binding protein. The KID domain contains the PKA phosphorylation site (Ser-119) that is essential for signal-dependent activation. Supporting Evidence: PMID:11522779 SRCAP functions as a coactivator for PKA-activated factors such as CREB PMID:1655749 ATF-1 is as active as CREB in its ability to mediate the transcriptional effects of PKA
GO:0035497 cAMP response element binding	IBA GO_REF:0000033	ACCEPT	Summary: CRE binding is the defining molecular function of CREB1. The protein binds the palindromic CRE sequence (TGACGTCA) as dimers via its bZIP domain. This is the core DNA binding specificity of CREB1. Reason: Core molecular function. CRE binding is what distinguishes CREB family members from other bZIP transcription factors. Well-supported by structural and biochemical studies. Supporting Evidence: PMID:19861239 Using chromatin immunoprecipitation assays we showed comparable in vivo cJun and CREB1 binding to the G-CRE region PMID:8798441 Electrophoretic mobility shift assays with the bcl-2 CRE demonstrated complexes with mobilities identical to those with a consensus CRE
GO:1990589 ATF4-CREB1 transcription factor complex	IBA GO_REF:0000033	ACCEPT	Summary: CREB1 forms heterodimeric complexes with ATF4, particularly in the context of ER stress response. The ATF4-CREB1 complex activates genes like GRP78/BiP through ATF/CRE sites (PMID:12871976). Reason: Valid cellular component annotation. CREB1 can heterodimerize with other bZIP factors including ATF4, ATF1, and CREM through its leucine zipper domain. Supporting Evidence: PMID:12871976 we have identified the closely related ATF1 and CREB1 as nuclear co-factors that form in vivo complexes with endogenous ATF4
GO:0003677 DNA binding	IEA GO_REF:0000120	ACCEPT	Summary: CREB1 binds DNA via its bZIP domain. While accurate, this is a parent term of the more specific GO:0035497 (cAMP response element binding) which better describes CREB1's DNA binding specificity. Reason: Accurate but less informative than GO:0035497. The IEA annotation based on domain (bZIP) is correct. Keep as it provides broader context alongside the more specific CRE binding annotation.
GO:0003700 DNA-binding transcription factor activity	IEA GO_REF:0000120	ACCEPT	Summary: CREB1 is a DNA-binding transcription factor. This is a parent term of the more specific GO:0000981 (RNA polymerase II-specific) annotation. Reason: Accurate general annotation. The more specific child term GO:0000981 is also present and provides better specificity.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: CREB1 is a nuclear transcription factor. Nuclear localization is required for its function and is enhanced by sumoylation at Lys-290 (UniProt). Reason: Core cellular component. CREB1 functions in the nucleus to regulate transcription. Well-supported by multiple experimental studies.
GO:0006355 regulation of DNA-templated transcription	IEA GO_REF:0000002	ACCEPT	Summary: CREB1 regulates DNA-templated transcription. This is a parent term of more specific process annotations already present. Reason: Accurate general annotation inferred from InterPro domains. More specific annotations (GO:0006357, GO:0045944) provide better detail.
GO:0030154 cell differentiation	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: CREB1 plays roles in differentiation of various cell types including adipocytes and neurons, as a downstream effector of differentiation signals that activate cAMP/PKA pathways. Reason: CREB1 participates in differentiation but this is a downstream consequence of its transcriptional activity rather than a core function. It regulates differentiation genes in response to upstream signals.
GO:0048511 rhythmic process	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This IEA annotation is based on the UniProt keyword "Biological rhythms". While CREB1 can regulate some clock gene expression and phosphorylation of Ser-119 and Ser-128 in the suprachiasmatic nucleus (SCN) participates in circadian rhythm generation, rhythmic process is NOT a core function of CREB1. The deep research review covers neuronal activity-dependent transcription, metabolic regulation, cancer, and immune function without emphasis on circadian rhythms. Reason: CREB1's core function is cAMP-responsive transcription. While it may regulate some clock genes, this is context-dependent and not a defining function. The annotation appears to derive from studies showing CREB involvement in SCN signaling, but rhythm regulation is downstream of its core transcription factor activity.
GO:0005515 protein binding	IPI PMID:10722738 cAMP-independent activation of the adenovirus type 12 E2 pro...	REMOVE	Summary: Generic protein binding annotation from interaction with adenovirus E1A protein. This uninformative term should be replaced with more specific binding terms. Reason: GO:0005515 (protein binding) is uninformative per GO curation guidelines. CREB1 has multiple specific binding partners (CBP/p300, CRTCs, other bZIP factors) that are better captured by more specific terms. Supporting Evidence: PMID:10722738 cAMP-independent activation of the adenovirus type 12 E2 promoter correlates with the recruitment of CREB-1/ATF-1, E1A(12S), and CBP to the E2-CRE.
GO:0005515 protein binding	IPI PMID:15733869 Serum/glucocorticoid-inducible kinase can phosphorylate the ...	REMOVE	Summary: Generic protein binding from interaction with SGK1 kinase. SGK1 phosphorylates CREB1 at Ser-119. Reason: Uninformative generic term. The interaction with SGK1 is a kinase-substrate relationship, not a generic binding interaction. Supporting Evidence: PMID:15733869 Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic AMP response element binding protein, CREB.
GO:0005515 protein binding	IPI PMID:15964553 TSSK5, a novel member of the testis-specific serine/threonin...	REMOVE	Summary: Generic protein binding from interaction with TSSK4 kinase. TSSK4 phosphorylates CREB1 at Ser-119. Reason: Uninformative generic term. This is a kinase-substrate relationship. Supporting Evidence: PMID:15964553 TSSK5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates CREB at Ser-133, and stimulates the CRE/CREB responsive pathway.
GO:0005515 protein binding	IPI PMID:16799563 An ARC/Mediator subunit required for SREBP control of choles...	REMOVE	Summary: Generic protein binding from interaction with CREBBP (CBP). This is a functionally important interaction - phosphorylated CREB1 recruits CBP via KID-KIX interaction. Reason: Uninformative generic term. The CREB1-CBP interaction is better captured by more specific terms like GO:0001223 (transcription coactivator binding). Supporting Evidence: PMID:16799563 An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis.
GO:0005515 protein binding	IPI PMID:20102225 Identification of bZIP interaction partners of viral protein...	REMOVE	Summary: Generic protein binding from coiled-coil array study identifying bZIP interaction partners. Identified interactions with viral proteins HBZ, MEQ and cellular bZIP factors ATF1, NFIL3. Reason: Uninformative generic term. The specific interactions with other bZIP factors are better captured by GO:0042802 (identical protein binding) for homodimerization or specific heterodimer annotations. Supporting Evidence: PMID:20102225 Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
GO:0005515 protein binding	IPI PMID:20159610 PML/RARalpha targets promoter regions containing PU.1 consen...	REMOVE	Summary: Generic protein binding from interaction with MEIS1. Reason: Uninformative generic term per GO curation guidelines. Supporting Evidence: PMID:20159610 PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia.
GO:0005515 protein binding	IPI PMID:20541704 GSK-3 promotes conditional association of CREB and its coact...	REMOVE	Summary: Generic protein binding from study showing GSK-3 promotes CREB association with MEIS1 for HOX-mediated transcription. Reason: Uninformative generic term. The biological context (transcriptional co-regulation) is better captured by other annotations. Supporting Evidence: PMID:20541704 GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.
GO:0005515 protein binding	IPI PMID:20936779 A human MAP kinase interactome.	REMOVE	Summary: Generic protein binding from MAP kinase interactome study with CRTC1. Reason: Uninformative generic term. CRTC1 is a CREB coactivator - this functional relationship is better represented by specific annotations. Supporting Evidence: PMID:20936779 A human MAP kinase interactome.
GO:0005515 protein binding	IPI PMID:21418524 Substrate preference and phosphatidylinositol monophosphate ...	REMOVE	Summary: Generic protein binding from study with PASKIN (PASK) kinase. Reason: Uninformative generic term. Supporting Evidence: PMID:21418524 2011 Apr 8. Substrate preference and phosphatidylinositol monophosphate inhibition of the catalytic domain of the Per-Arnt-Sim domain kinase PASKIN.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	REMOVE	Summary: Generic protein binding from liver protein interactome study with TSSK4. Reason: Uninformative generic term. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver.
GO:0005515 protein binding	IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ...	REMOVE	Summary: Generic protein binding from chromatin-associated transcription factor complex study. Reason: Uninformative generic term. Supporting Evidence: PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Generic protein binding from human binary protein interactome reference map. Reason: Uninformative generic term from high-throughput study. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: Generic protein binding from neurodegenerative disease protein interactome study showing interaction with HTT (huntingtin). Reason: Uninformative generic term. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0042802 identical protein binding	IPI PMID:20102225 Identification of bZIP interaction partners of viral protein...	ACCEPT	Summary: CREB1 homodimerization via the leucine zipper domain. CREB1 functions as homodimers or heterodimers when binding DNA. Reason: Valid molecular function. Dimerization via the leucine zipper is essential for DNA binding and transcriptional activity. More informative than generic protein binding. Supporting Evidence: PMID:1655749 ATF-1 is capable of dimerizing with CREB. Both ATF-1 homodimers and ATF-1/CREB heterodimers bind to the CRE PMID:20102225 Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
GO:0042802 identical protein binding	IPI PMID:23661758 Networks of bZIP protein-protein interactions diversified ov...	ACCEPT	Summary: CREB1 homodimerization from bZIP protein-protein interaction network study. Reason: Valid molecular function annotation for homodimerization. Supporting Evidence: PMID:23661758 Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
GO:0042802 identical protein binding	IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ...	ACCEPT	Summary: CREB1 homodimerization from chromatin-associated transcription factor complex study. Reason: Valid molecular function annotation for homodimerization. Supporting Evidence: PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
GO:0000785 chromatin	IEA GO_REF:0000120	ACCEPT	Summary: CREB1 associates with chromatin at CRE-containing promoters and enhancers. Supported by ChIP studies showing CREB1 occupancy at target gene promoters. Reason: Valid cellular component. CREB1 binds chromatin at CRE sites to regulate transcription.
GO:0000976 transcription cis-regulatory region binding	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 binds cis-regulatory regions containing CRE elements. This is a parent term of the more specific CRE binding annotation. Reason: Accurate general annotation. More specific term GO:0035497 (cAMP response element binding) provides better detail.
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 binds sequence-specifically to CRE elements in Pol II-transcribed gene promoters. Reason: Core molecular function describing CREB1's DNA binding specificity at Pol II promoters.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate of IBA annotation. CREB1 is a Pol II-specific transcription factor. Reason: Core molecular function. IEA annotation consistent with IBA annotation.
GO:0001223 transcription coactivator binding	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 binds transcriptional coactivators CBP/p300 and CRTCs. The KID-KIX interaction between phosphorylated CREB1 and CBP/p300 is essential for transcriptional activation. Reason: Core molecular function. Coactivator recruitment is essential for CREB1-mediated transcription. Supporting Evidence: PMID:11522779 SRCAP binds to CBP amino acids 280-460, a region that is important for CBP to function as a coactivator for CREB
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 functions primarily as a transcriptional activator when phosphorylated. Upon Ser-119 phosphorylation, it recruits CBP/p300 to activate target gene transcription. Reason: Core molecular function. CREB1 is an activator of transcription in response to cAMP signaling.
GO:0001666 response to hypoxia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 responds to hypoxia through sumoylation and other regulatory mechanisms. Hypoxia enhances CREB1 sumoylation, promoting nuclear localization and stabilization (UniProt, PMID:12552083). Reason: Valid biological process but context-dependent rather than core function. CREB1 is regulated by hypoxia but hypoxia response is not its primary role.
GO:0005667 transcription regulator complex	IEA GO_REF:0000120	ACCEPT	Summary: CREB1 participates in transcription regulatory complexes with coactivators (CBP/p300, CRTCs) and can form heterodimers with other bZIP factors. Reason: Valid cellular component. CREB1 functions within multiprotein transcriptional complexes.
GO:0005759 mitochondrial matrix	IEA GO_REF:0000107	UNDECIDED	Summary: Some studies suggest CREB1 may have mitochondrial functions, but this is not well-established for the nuclear transcription factor. CREB1 primarily functions in the nucleus. Reason: The evidence for mitochondrial matrix localization of CREB1 is limited. CREB1 is primarily a nuclear protein. Requires further investigation.
GO:0006357 regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate annotation. CREB1 regulates Pol II transcription. Reason: Core biological process. IEA annotation consistent with IBA annotation.
GO:0007179 transforming growth factor beta receptor signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may be involved in TGF-beta signaling as a downstream transcriptional effector, but this is not a core pathway for CREB1. Reason: CREB1 may participate in TGF-beta responses through cross-talk with other signaling pathways, but TGF-beta signaling is not a core CREB1 function.
GO:0007613 memory	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 plays important roles in memory formation through activity-dependent gene expression in neurons. This is supported by extensive literature on CREB in synaptic plasticity and long-term memory. Reason: Well-documented role in memory but this is a neuron-specific phenotypic outcome of CREB1's transcriptional activity rather than a molecular function. Important for understanding CREB1 biology but downstream of core function.
GO:0007623 circadian rhythm	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: CREB1 phosphorylation in the suprachiasmatic nucleus (SCN) participates in circadian rhythm generation. However, circadian rhythm is not a core function of CREB1 - it is a context-dependent downstream effect of its transcriptional activity in specific cell types. Reason: While CREB1 may regulate clock genes in the SCN, circadian rhythm is not a core function. The deep research review focuses on cAMP-responsive transcription, neuronal plasticity, metabolism, cancer, and immune function without emphasis on circadian rhythms. This appears to be over-annotation based on tissue-specific phenotypic effects.
GO:0008542 visual learning	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may participate in visual learning through activity-dependent gene expression, similar to its role in memory formation. Reason: Phenotypic outcome of CREB1 transcriptional activity in specific neuronal contexts. Not a core molecular or cellular function.
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may be activated by various xenobiotic stimuli that signal through cAMP/PKA pathways. Reason: Context-dependent response, not a core function. CREB1 responds to many stimuli that activate upstream kinases.
GO:0010629 negative regulation of gene expression	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 can negatively regulate gene expression in certain contexts, though it primarily functions as a transcriptional activator. Reason: CREB1 primarily activates transcription but can have repressive effects in specific contexts. Not the primary mode of action.
GO:0014823 response to activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 is activated by neuronal activity through Ca2+/CaMK and other pathways, mediating activity-dependent gene expression. Reason: Important for understanding CREB1's role in neurons but context-dependent. Core function is cAMP-responsive transcription.
GO:0030424 axon	IEA GO_REF:0000107	UNDECIDED	Summary: CREB1 may be detected in axons but its primary site of function is the nucleus where it regulates transcription. Reason: CREB1 is primarily a nuclear protein. Axonal localization would be unusual and requires verification. May reflect transport or non-canonical function.
GO:0030544 Hsp70 protein binding	IEA GO_REF:0000107	UNDECIDED	Summary: CREB1 may interact with Hsp70 chaperones for protein folding or stability. Reason: Limited evidence for functional significance of Hsp70 binding. May represent general chaperone interaction rather than specific functional binding.
GO:0032916 positive regulation of transforming growth factor beta3 production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may regulate TGF-beta3 expression through CRE elements in the TGF-beta3 promoter. Reason: Specific downstream target regulation, not a core function. CREB1 regulates many target genes.
GO:0033762 response to glucagon	IEA GO_REF:0000107	ACCEPT	Summary: Glucagon signals through cAMP/PKA to activate CREB1 in hepatocytes, inducing gluconeogenic genes like PEPCK. This is a well-characterized metabolic role of CREB1. Reason: Well-documented response - glucagon activates CREB1 through cAMP/PKA in liver to regulate gluconeogenesis. Directly relevant to core cAMP-responsive function. Supporting Evidence: PMID:11522779 The phosphoenolpyruvate carboxykinase (PEPCK) promoter was used as a model system to explore the role of SRCAP in the regulation of transcription mediated by factors that utilize CBP as a coactivator
GO:0034670 chemotaxis to arachidonate	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may be involved in arachidonate-mediated chemotaxis signaling. Reason: Context-dependent response, not a core CREB1 function.
GO:0035035 histone acetyltransferase binding	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 binds histone acetyltransferases CBP/p300 when phosphorylated at Ser-119. This is a core mechanism for transcriptional activation. Reason: Core molecular function. CBP and p300 are histone acetyltransferases that CREB1 recruits to activate transcription. The KID-KIX interaction is essential for CREB-mediated gene activation. Supporting Evidence: PMID:11522779 SRCAP binds to CBP amino acids 280-460, a region that is important for CBP to function as a coactivator for CREB
GO:0035094 response to nicotine	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may be activated by nicotine through neuronal signaling pathways. Reason: Context-dependent response to a specific stimulus, not a core function.
GO:0035497 cAMP response element binding	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate of IBA annotation. CRE binding is the defining DNA binding specificity of CREB1. Reason: Core molecular function. IEA annotation consistent with IBA annotation.
GO:0036017 response to erythropoietin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may be involved in erythropoietin signaling responses. Reason: Context-dependent signaling response, not a core function.
GO:0036120 cellular response to platelet-derived growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may be activated by PDGF signaling through MAPK/RSK pathways. Reason: Context-dependent growth factor response. CREB1 responds to many upstream signals.
GO:0042220 response to cocaine	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 is activated by cocaine in reward circuits through dopamine signaling and cAMP/PKA pathways. Reason: Context-dependent drug response in neurons, not a core function.
GO:0042981 regulation of apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 regulates genes involved in apoptosis including BCL-2 family members (PMID:8798441). It generally promotes cell survival. Reason: CREB1 regulates apoptosis-related genes but this is a downstream phenotypic effect of its transcriptional activity, not a core function. Supporting Evidence: PMID:8798441 CREB proteins function as positive regulators of the translocated bcl-2 allele in t(14;18) lymphomas
GO:0043065 positive regulation of apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 can positively regulate apoptosis in certain contexts, though it more commonly promotes survival. Reason: Context-dependent effect on apoptosis. CREB1 primarily promotes survival but can have pro-apoptotic effects in some settings.
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: CREB1 generally promotes cell survival through activation of anti-apoptotic genes like BCL-2. Reason: CREB1 has pro-survival effects through transcriptional regulation of BCL-2 and other genes, but this is a downstream phenotypic effect. Supporting Evidence: PMID:8798441 CREB proteins function as positive regulators of the translocated bcl-2 allele
GO:0043278 response to morphine	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 is activated by morphine through opioid receptor signaling. Reason: Context-dependent drug response, not a core function.
GO:0043565 sequence-specific DNA binding	IEA GO_REF:0000120	ACCEPT	Summary: CREB1 binds DNA in a sequence-specific manner to CRE elements. Parent term of more specific annotations. Reason: Core molecular function. CREB1 recognizes the CRE sequence specifically.
GO:0045471 response to ethanol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may respond to ethanol through various neuronal signaling pathways. Reason: Context-dependent drug response, not a core function.
GO:0045600 positive regulation of fat cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 promotes adipocyte differentiation through regulation of adipogenic genes in response to cAMP signaling. Reason: Cell type-specific differentiation role, downstream of core transcriptional function.
GO:0045722 positive regulation of gluconeogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 activates gluconeogenic genes like PEPCK in response to glucagon/cAMP signaling in hepatocytes. Reason: Important metabolic role in liver but tissue-specific downstream effect of core cAMP-responsive transcription function. Supporting Evidence: PMID:11522779 The phosphoenolpyruvate carboxykinase (PEPCK) promoter was used as a model system
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 positively regulates transcription when activated by phosphorylation. Reason: Core biological process. CREB1 is primarily a transcriptional activator.
GO:0045899 positive regulation of RNA polymerase II transcription preinitiation complex assembly	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 may facilitate preinitiation complex assembly through recruitment of coactivators that interact with basal transcription machinery. Reason: Mechanistically relevant to CREB1's role in transcriptional activation.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 activates Pol II-dependent transcription when phosphorylated. Reason: Core biological process directly related to CREB1's molecular function as a transcriptional activator.
GO:0046889 positive regulation of lipid biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may regulate lipogenic gene expression in metabolic contexts. Reason: Metabolic downstream effect, not a core function.
GO:0048145 regulation of fibroblast proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may regulate fibroblast proliferation through growth factor signaling. Reason: Cell type-specific phenotypic effect, not a core function.
GO:0050821 protein stabilization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may regulate expression of genes involved in protein stability. CREB1 itself is stabilized by sumoylation. Reason: Indirect effect through transcriptional regulation or relates to CREB1's own regulation, not a core function.
GO:0060251 regulation of glial cell proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may regulate glial cell proliferation through neuronal signaling. Reason: Cell type-specific phenotypic effect, not a core function.
GO:0071300 cellular response to retinoic acid	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may participate in retinoic acid responses through cross-talk with other signaling pathways. Reason: Context-dependent signaling response, not a core function.
GO:0071363 cellular response to growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 is activated by various growth factors through MAPK/RSK and other signaling pathways. Reason: General response category. Core function is cAMP-responsive transcription, but CREB1 also responds to growth factor signals.
GO:0071398 cellular response to fatty acid	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may respond to fatty acid signaling in metabolic contexts. Reason: Context-dependent metabolic response, not a core function.
GO:0071560 cellular response to transforming growth factor beta stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may participate in TGF-beta responses. Reason: Context-dependent signaling response, not a core function.
GO:1900273 positive regulation of long-term synaptic potentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 plays important roles in long-term potentiation (LTP) through activity-dependent gene expression required for synaptic plasticity. Reason: Well-documented neuronal function but this is a phenotypic outcome of CREB1's transcriptional activity in neurons, not a core molecular function.
GO:1902065 response to L-glutamate	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 is activated by glutamate signaling through Ca2+/CaMK pathways in neurons. Reason: Neuron-specific signaling response, not a core function.
GO:1903494 response to dehydroepiandrosterone	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may respond to DHEA signaling. Reason: Context-dependent hormonal response, not a core function.
GO:1904181 positive regulation of membrane depolarization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may regulate genes involved in neuronal excitability. Reason: Downstream phenotypic effect in neurons, not a core function.
GO:1990090 cellular response to nerve growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 is activated by NGF through MAPK/RSK pathways in neurons. Reason: Neuron-specific growth factor response, not a core function.
GO:1990314 cellular response to insulin-like growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may be activated by IGF signaling through PI3K/AKT pathway. Reason: Context-dependent growth factor response, not a core function.
GO:1990589 ATF4-CREB1 transcription factor complex	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate of IBA annotation. CREB1 forms complexes with ATF4. Reason: Valid cellular component. IEA annotation consistent with IBA annotation.
GO:1990763 arrestin family protein binding	IEA GO_REF:0000107	ACCEPT	Summary: CREB1 interacts with beta-arrestin1 (ARRB1) which has a nuclear function in GPCR signaling and histone acetylation (PMID:16325578). Reason: Specific protein binding annotation more informative than generic protein binding. ARRB1 interaction is functionally relevant for CREB-dependent transcription.
GO:1990910 response to hypobaric hypoxia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may respond to hypoxic stress. Reason: Context-dependent stress response, not a core function.
GO:2000224 regulation of testosterone biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CREB1 may regulate steroidogenic gene expression in gonadal cells. Reason: Tissue-specific downstream effect, not a core function.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: CREB1 localizes to the nucleoplasm where it functions as a transcription factor. Reason: Core cellular component. IDA annotation from immunofluorescence data.
GO:0005634 nucleus	NAS PMID:12871976 Induction of Grp78/BiP by translational block: activation of...	ACCEPT	Summary: CREB1 is a nuclear transcription factor. PMID:12871976 identifies CREB1 as a nuclear co-factor that forms complexes with ATF4. Reason: Core cellular component supported by literature. Supporting Evidence: PMID:12871976 we have identified the closely related ATF1 and CREB1 as nuclear co-factors that form in vivo complexes with endogenous ATF4
GO:0005634 nucleus	NAS PMID:1655749 The cAMP-regulated enhancer-binding protein ATF-1 activates ...	ACCEPT	Summary: CREB1 is a nuclear transcription factor. Reason: Core cellular component. Supporting Evidence: PMID:1655749 The cAMP-regulated enhancer-binding protein ATF-1 activates transcription in response to cAMP-dependent protein kinase A.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:1655749 The cAMP-regulated enhancer-binding protein ATF-1 activates ...	ACCEPT	Summary: PMID:1655749 demonstrates that CREB family members (ATF-1 and CREB) activate transcription in response to PKA. Reason: Core biological process. Direct experimental evidence for transcriptional activation. Supporting Evidence: PMID:1655749 ATF-1 is as active as CREB in its ability to mediate the transcriptional effects of PKA
GO:0005634 nucleus	NAS PMID:20102225 Identification of bZIP interaction partners of viral protein...	ACCEPT	Summary: CREB1 is a nuclear protein. Reason: Core cellular component. Supporting Evidence: PMID:20102225 Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
GO:0006357 regulation of transcription by RNA polymerase II	NAS PMID:20102225 Identification of bZIP interaction partners of viral protein...	ACCEPT	Summary: CREB1 regulates Pol II transcription. Reason: Core biological process. Supporting Evidence: PMID:20102225 Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IDA PMID:11522779 Regulation of cAMP-responsive element-binding protein-mediat...	ACCEPT	Summary: PMID:11522779 demonstrates that CREB mediates PKA-activated transcription through CRE elements in the PEPCK promoter. Reason: Core molecular function with direct experimental evidence. Supporting Evidence: PMID:11522779 SRCAP functions as a coactivator for PKA-activated factors such as CREB
GO:0005634 nucleus	IDA PMID:11522779 Regulation of cAMP-responsive element-binding protein-mediat...	ACCEPT	Summary: CREB1 functions in the nucleus. Reason: Core cellular component. Supporting Evidence: PMID:11522779 2001 Aug 24. Regulation of cAMP-responsive element-binding protein-mediated transcription by the SNF2/SWI-related protein, SRCAP.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:11522779 Regulation of cAMP-responsive element-binding protein-mediat...	ACCEPT	Summary: PMID:11522779 shows CREB activates Pol II transcription at the PEPCK promoter. Reason: Core biological process with direct experimental evidence. Supporting Evidence: PMID:11522779 transcription of a PEPCK chloramphenicol acetyltransferase (CAT) reporter gene activated by protein kinase A (PKA) is enhanced 7-fold by SRCAP
GO:0141156 cAMP/PKA signal transduction	IDA PMID:11522779 Regulation of cAMP-responsive element-binding protein-mediat...	ACCEPT	Summary: PMID:11522779 demonstrates CREB's role as a downstream effector of PKA signaling. Reason: Core biological process with direct experimental evidence. Supporting Evidence: PMID:11522779 SRCAP functions as a coactivator for PKA-activated factors such as CREB
GO:0141156 cAMP/PKA signal transduction	IDA PMID:25644539 Adenosine derived from ecto-nucleotidases in calcific aortic...	ACCEPT	Summary: PMID:25644539 demonstrates CREB1 involvement in cAMP/PKA signaling in the context of aortic valve calcification. Reason: Core biological process with experimental evidence. Supporting Evidence: PMID:25644539 Feb 2. Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-199298	ACCEPT	Summary: Reactome pathway for AKT phosphorylation of CREB1 places CREB1 in nucleoplasm. Reason: Core cellular component supported by pathway database.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-199895	ACCEPT	Summary: Reactome pathway for RSK1/2/3 phosphorylation of CREB. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-199917	ACCEPT	Summary: Reactome pathway for MAPKAPK2 phosphorylation of CREB. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-199935	ACCEPT	Summary: Reactome pathway for MSK1 activation of CREB. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-2399996	ACCEPT	Summary: Reactome pathway for AKT1 E17K mutant phosphorylation of CREB1. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-442724	ACCEPT	Summary: Reactome pathway for RSK phosphorylation of CREB1. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9612501	ACCEPT	Summary: Reactome pathway for SGK phosphorylation of CREB1. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9612514	ACCEPT	Summary: Reactome pathway for p-S133 CREB binding to EGR1 promoter. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9613451	ACCEPT	Summary: Reactome pathway for CREB1 binding to ID1 and ID3 genes. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9623341	ACCEPT	Summary: Reactome pathway for CREB1 binding to CCND1 promoter. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9662708	ACCEPT	Summary: Reactome pathway for CREB binding to IL6 promoter. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9664332	ACCEPT	Summary: Reactome pathway for CREB1 binding to IL-10 promoter. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9824653	ACCEPT	Summary: Reactome pathway for CREB1 binding to MITF promoter. Reason: Core cellular component.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9825848	ACCEPT	Summary: Reactome pathway for CREB1 at DCT promoter. Reason: Core cellular component.
GO:0043066 negative regulation of apoptotic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CREB1 promotes cell survival through activation of anti-apoptotic genes like BCL-2. Reason: Downstream phenotypic effect of transcriptional activity.
GO:0042789 mRNA transcription by RNA polymerase II	IDA PMID:25644539 Adenosine derived from ecto-nucleotidases in calcific aortic...	ACCEPT	Summary: CREB1 mediates mRNA transcription by Pol II. Reason: Core biological process related to transcriptional function. Supporting Evidence: PMID:25644539 Feb 2. Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor.
GO:1904322 cellular response to forskolin	IDA PMID:25644539 Adenosine derived from ecto-nucleotidases in calcific aortic...	ACCEPT	Summary: Forskolin activates adenylyl cyclase and cAMP/PKA signaling, which activates CREB1. CREB1 is a key mediator of forskolin responses. Reason: Directly relevant to CREB1's core function in cAMP signaling. Forskolin is a standard tool for activating CREB through the cAMP/PKA pathway. Supporting Evidence: PMID:25644539 Feb 2. Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor.
GO:0014074 response to purine-containing compound	IDA PMID:25644539 Adenosine derived from ecto-nucleotidases in calcific aortic...	KEEP AS NON CORE	Summary: CREB1 responds to adenosine and other purine compounds through cAMP signaling. Reason: Related to cAMP signaling but general response category. Supporting Evidence: PMID:25644539 Feb 2. Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor.
GO:1990837 sequence-specific double-stranded DNA binding	IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ...	ACCEPT	Summary: PMID:28473536 analyzed DNA binding specificities of transcription factors including CREB1. Reason: Core molecular function describing DNA binding specificity. Supporting Evidence: PMID:28473536 Impact of cytosine methylation on DNA binding specificities of human transcription factors.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	ISS GO_REF:0000024	ACCEPT	Summary: CREB1 is a transcriptional activator. Reason: Core molecular function.
GO:0000785 chromatin	ISA GO_REF:0000113	ACCEPT	Summary: CREB1 associates with chromatin at CRE-containing promoters. Reason: Valid cellular component.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	ISA GO_REF:0000113	ACCEPT	Summary: CREB1 is a Pol II-specific transcription factor based on TFClass database. Reason: Core molecular function.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IDA PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream...	ACCEPT	Summary: PMID:19861239 shows CREB1 activates gamma-globin gene expression through the G-CRE element. Reason: Core molecular function with direct experimental evidence. Supporting Evidence: PMID:19861239 enforced expression studies with pLen-cJun and a Ggamma-promoter (-1500 to +36) luciferase reporter were completed; we observed a concentration-dependent increase in luciferase activity with pLen-cJun similar to that produced by CREB1 enforced expression
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	ACCEPT	Summary: CREB1 activates Pol II transcription. Reason: Core biological process.
GO:0071300 cellular response to retinoic acid	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CREB1 may participate in retinoic acid responses. Reason: Context-dependent signaling response.
GO:1990589 ATF4-CREB1 transcription factor complex	IDA PMID:12871976 Induction of Grp78/BiP by translational block: activation of...	ACCEPT	Summary: PMID:12871976 identifies CREB1 as forming complexes with ATF4 that activate the Grp78 promoter through ATF/CRE sites. Reason: Valid cellular component with direct experimental evidence. Supporting Evidence: PMID:12871976 we have identified the closely related ATF1 and CREB1 as nuclear co-factors that form in vivo complexes with endogenous ATF4
GO:0019899 enzyme binding	IPI PMID:23382074 A high-confidence interaction map identifies SIRT1 as a medi...	ACCEPT	Summary: PMID:23382074 identifies CREB1 interaction with SIRT1 deacetylase. More informative than generic protein binding. Reason: Specific binding annotation. CREB1 interacts with various enzymes that regulate its activity. Supporting Evidence: PMID:23382074 Feb 4. A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.
GO:0007623 circadian rhythm	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Circadian rhythm annotation based on sequence similarity to mouse CREB1. While CREB1 participates in SCN signaling, circadian rhythm is not a core function. Reason: Over-annotation. CREB1's core function is cAMP-responsive transcription. Circadian rhythm involvement is tissue-specific and downstream of core function.
GO:0033762 response to glucagon	ISS GO_REF:0000024	ACCEPT	Summary: Glucagon response is well-documented for CREB1 in hepatocytes. Reason: Well-characterized response directly related to cAMP/PKA signaling function.
GO:0045600 positive regulation of fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CREB1 promotes adipocyte differentiation. Reason: Cell type-specific downstream effect.
GO:0045893 positive regulation of DNA-templated transcription	ISS GO_REF:0000024	ACCEPT	Summary: CREB1 activates transcription. Reason: Core biological process.
GO:0046889 positive regulation of lipid biosynthetic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CREB1 may regulate lipogenic genes. Reason: Metabolic downstream effect.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IDA PMID:9065434 Constitutive binding of the transcription factor interleukin...	ACCEPT	Summary: PMID:9065434 demonstrates CREB binding to the IL-2 promoter CRE. Reason: Core molecular function with experimental evidence. Supporting Evidence: PMID:9065434 Constitutive binding of the transcription factor interleukin-2 (IL-2) enhancer binding factor to the IL-2 promoter.
GO:0005515 protein binding	IPI PMID:18160048 Lyl1 interacts with CREB1 and alters expression of CREB1 tar...	REMOVE	Summary: Generic protein binding from interaction with LYL1. Reason: Uninformative generic term. Supporting Evidence: PMID:18160048 Lyl1 interacts with CREB1 and alters expression of CREB1 target genes.
GO:0050821 protein stabilization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CREB1 may contribute to protein stabilization. Reason: Indirect effect, not a core function.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IDA PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream...	ACCEPT	Summary: PMID:19861239 demonstrates CREB1 transcription factor activity at gamma-globin promoter. Reason: Core molecular function with experimental evidence. Supporting Evidence: PMID:19861239 Using chromatin immunoprecipitation assays we showed comparable in vivo cJun and CREB1 binding to the G-CRE region
GO:0010944 negative regulation of transcription by competitive promoter binding	IDA PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream...	ACCEPT	Summary: PMID:19861239 shows competitive binding at the gamma-globin CRE where CREB1 and cJun can compete for binding. Reason: Valid regulatory mechanism - competition between transcription factors at shared binding sites. Supporting Evidence: PMID:19861239 Protein-protein interactions were confirmed between cJun/ATF-2 and CREB1/ATF-2 but not between CREB1 and cJun
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream...	ACCEPT	Summary: PMID:19861239 shows CREB1 activates gamma-globin transcription. Reason: Core biological process with experimental evidence. Supporting Evidence: PMID:19861239 we observed a concentration-dependent increase in luciferase activity with pLen-cJun similar to that produced by CREB1 enforced expression
GO:0000791 euchromatin	IDA PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream...	ACCEPT	Summary: PMID:19861239 shows CREB1 binding to the actively transcribed gamma-globin locus in euchromatin. Reason: Valid cellular component - CREB1 binds actively transcribed chromatin regions. Supporting Evidence: PMID:19861239 Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IDA PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream...	ACCEPT	Summary: PMID:19861239 demonstrates CREB1 binding to the gamma-globin G-CRE. Reason: Core molecular function with experimental evidence. Supporting Evidence: PMID:19861239 we observed cJun and CREB1 binding to the G-CRE in vitro by electrophoretic mobility shift assay
GO:0035497 cAMP response element binding	IDA PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream...	ACCEPT	Summary: PMID:19861239 demonstrates CREB1 binding to the G-CRE element. Reason: Core molecular function with direct experimental evidence. Supporting Evidence: PMID:19861239 Using chromatin immunoprecipitation assays we showed comparable in vivo cJun and CREB1 binding to the G-CRE region
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	IPI PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream...	ACCEPT	Summary: PMID:19861239 shows CREB1 interacts with c-Jun at the gamma-globin promoter. Reason: Valid molecular function - CREB1 interacts with other transcription factors. Supporting Evidence: PMID:19861239 Promoter pull-down assay followed by sequential western blot analysis confirmed co-localization of cJun, CREB1, and ATF-2 on the G-CRE
GO:0005515 protein binding	IPI PMID:21172805 TOX3 is a neuronal survival factor that induces transcriptio...	REMOVE	Summary: Generic protein binding from interaction with TOX3. Reason: Uninformative generic term. Supporting Evidence: PMID:21172805 Dec 15. TOX3 is a neuronal survival factor that induces transcription depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex.
GO:0005515 protein binding	IPI PMID:18316612 Molecular basis of nuclear factor-kappaB activation by astro...	REMOVE	Summary: Generic protein binding from interaction with AEG-1. Reason: Uninformative generic term. Supporting Evidence: PMID:18316612 Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1.
GO:0005515 protein binding	IPI PMID:16325578 A nuclear function of beta-arrestin1 in GPCR signaling: regu...	REMOVE	Summary: Generic protein binding from interaction with beta-arrestin1 (ARRB1). Reason: Uninformative generic term. The ARRB1 interaction is better captured by GO:1990763 (arrestin family protein binding). Supporting Evidence: PMID:16325578 A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription.
GO:0003700 DNA-binding transcription factor activity	IDA PMID:8798441 CREB proteins function as positive regulators of the translo...	ACCEPT	Summary: PMID:8798441 demonstrates CREB binding to the bcl-2 CRE and transcriptional activation of the bcl-2 promoter. Reason: Core molecular function with experimental evidence. Supporting Evidence: PMID:8798441 Electrophoretic mobility shift assays with the bcl-2 CRE demonstrated complexes with mobilities identical to those with a consensus CRE
GO:0005634 nucleus	IDA PMID:8798441 CREB proteins function as positive regulators of the translo...	ACCEPT	Summary: CREB1 is a nuclear transcription factor. Reason: Core cellular component. Supporting Evidence: PMID:8798441 CREB proteins function as positive regulators of the translocated bcl-2 allele in t(14;18) lymphomas.
GO:0006468 protein phosphorylation	IDA PMID:8798441 CREB proteins function as positive regulators of the translo...	REMOVE	Summary: MISANNOTATION: CREB1 is a bZIP transcription factor that is extensively PHOSPHORYLATED by kinases (CaMK1/2/4, AKT, RPS6KA3/4/5, SGK1, TSSK4, HIPK2) at Ser-119, Ser-128, and Ser-257. PMID:8798441 describes "phosphorylated CREB was present in DHL-4 cells" - CREB1 is the SUBSTRATE of phosphorylation, not the enzyme. CREB1 has no kinase activity (EC number). This is a transcription factor that regulates bcl-2 expression when phosphorylated. The paper shows CREB1 being phosphorylated by upstream kinases like PKA and PKC, not CREB1 catalyzing phosphorylation. Reason: Incorrect annotation. CREB1 is phosphorylated by upstream kinases - it is a substrate, not an enzyme. CREB1 has no kinase domain or kinase activity. Supporting Evidence: PMID:8798441 Electrophoretic mobility shift assay with an antibody specific to the phosphorylated cAMP response-binding protein (CREB) demonstrated that phosphorylated CREB was present in DHL-4 cells
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:8798441 CREB proteins function as positive regulators of the translo...	ACCEPT	Summary: PMID:8798441 shows CREB proteins activate bcl-2 transcription through CRE elements. Reason: Core biological process with experimental evidence. Supporting Evidence: PMID:8798441 CREB proteins function as positive regulators of the translocated bcl-2 allele in t(14;18) lymphomas
GO:0005515 protein binding	IPI PMID:14506290 Identification of a family of cAMP response element-binding ...	REMOVE	Summary: Generic protein binding from interaction with CRTC3 coactivator. Reason: Uninformative generic term. CRTC interaction is better represented by GO:0001223 (transcription coactivator binding). Supporting Evidence: PMID:14506290 Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells.
GO:0007165 signal transduction	TAS PMID:2974179 Cyclic AMP-responsive DNA-binding protein - structure based ...	ACCEPT	Summary: PMID:2974179 describes the cloning of CREB and establishes its role in cAMP signal transduction. Reason: Core biological process. CREB1 is a key effector of cAMP signaling pathways. Supporting Evidence: PMID:2974179 Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA.

Core Functions

bZIP transcription factor that binds cAMP response elements (CRE; TGACGTCA) as homo- or heterodimers to activate transcription of target genes. Core defining function of CREB1 supported by extensive structural and functional studies.

Molecular Function:

DNA-binding transcription activator activity, RNA polymerase II-specific

Directly Involved In:

positive regulation of transcription by RNA polymerase II cAMP/PKA signal transduction

Cellular Locations:

nucleoplasm

Binds the palindromic CRE sequence (TGACGTCA) via its bZIP domain. This is the defining DNA binding specificity that distinguishes CREB family members from other bZIP transcription factors.

Molecular Function:

cAMP response element binding

Cellular Locations:

chromatin

Phosphorylation at Ser-119 by PKA and other kinases enables recruitment of CBP/p300 coactivators via the KID-KIX interaction. This coactivator binding is essential for CREB-mediated transcriptional activation.

Molecular Function:

transcription coactivator binding

Directly Involved In:

cAMP/PKA signal transduction

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000113

Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:1655749

The cAMP-regulated enhancer-binding protein ATF-1 activates transcription in response to cAMP-dependent protein kinase A.

ATF-1 and CREB can homodimerize and heterodimerize
Both bind CRE elements and mediate PKA-dependent transcription
ATF-1 is as active as CREB in mediating PKA transcriptional effects

PMID:11522779

Regulation of cAMP-responsive element-binding protein-mediated transcription by the SNF2/SWI-related protein, SRCAP.

SRCAP functions as a coactivator for PKA-activated CREB
CREB activates PEPCK promoter through CRE elements
SRCAP enhances PKA-activated transcription 7-fold

PMID:12871976

Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.

CREB1 forms complexes with ATF4 in the nucleus
ATF4-CREB1 complexes activate Grp78 promoter through ATF/CRE sites
ER stress induces CREB1 phosphorylation

PMID:8798441

CREB proteins function as positive regulators of the translocated bcl-2 allele in t(14;18) lymphomas.

Phosphorylated CREB binds bcl-2 CRE element
CREB activates bcl-2 promoter activity
PMA treatment increases phosphorylated CREB

PMID:19861239

cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.

CREB1 binds G-CRE element in vivo and in vitro
CREB1 activates gamma-globin transcription
CREB1 co-localizes with cJun and ATF-2 on the G-CRE

PMID:2974179

Cyclic AMP-responsive DNA-binding protein - structure based on a cloned placental cDNA.

Original cloning of CREB
Establishes CREB role in cAMP signal transduction

PMID:10722738

cAMP-independent activation of the adenovirus type 12 E2 promoter correlates with the recruitment of CREB-1/ATF-1, E1A(12S), and CBP to the E2-CRE.

PMID:15733869

Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic AMP response element binding protein, CREB.

PMID:15964553

TSSK5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates CREB at Ser-133, and stimulates the CRE/CREB responsive pathway.

PMID:16799563

An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis.

PMID:20102225

Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.

PMID:20159610

PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia.

PMID:20541704

GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.

PMID:20936779

A human MAP kinase interactome.

PMID:21418524

Substrate preference and phosphatidylinositol monophosphate inhibition of the catalytic domain of the Per-Arnt-Sim domain kinase PASKIN.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:25609649

Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:23661758

Networks of bZIP protein-protein interactions diversified over a billion years of evolution.

PMID:25644539

Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor.

PMID:28473536

Impact of cytosine methylation on DNA binding specificities of human transcription factors.

PMID:23382074

A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.

PMID:9065434

Constitutive binding of the transcription factor interleukin-2 (IL-2) enhancer binding factor to the IL-2 promoter.

PMID:18160048

Lyl1 interacts with CREB1 and alters expression of CREB1 target genes.

PMID:21172805

TOX3 is a neuronal survival factor that induces transcription depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex.

PMID:18316612

Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1.

PMID:16325578

A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription.

PMID:14506290

Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells.

Reactome:R-HSA-199298

AKT phosphorylation of CREB1

Reactome:R-HSA-199895

RSK1/2/3 phosphorylation of CREB

Reactome:R-HSA-199917

MAPKAPK2 phosphorylation of CREB

Reactome:R-HSA-199935

MSK1 activation of CREB

Reactome:R-HSA-2399996

AKT1 E17K mutant phosphorylation of CREB1

Reactome:R-HSA-442724

RSK phosphorylation of CREB1

Reactome:R-HSA-9612501

SGK phosphorylation of CREB1

Reactome:R-HSA-9612514

p-S133 CREB binding to EGR1 promoter

Reactome:R-HSA-9613451

CREB1 binding to ID1 and ID3 genes

Reactome:R-HSA-9623341

CREB1 binding to CCND1 promoter

Reactome:R-HSA-9662708

CREB binding to IL6 promoter

Reactome:R-HSA-9664332

CREB1 binding to IL-10 promoter

Reactome:R-HSA-9824653

CREB1 binding to MITF promoter

Reactome:R-HSA-9825848

CREB1 at DCT promoter

file:human/CREB1/CREB1-deep-research-falcon.md

Deep research report on CREB1

📚 Additional Documentation

Deep Research Falcon

(CREB1-deep-research-falcon.md)

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gene_info: Name=CREB1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the bZIP family. .
protein_domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); CREB1-like_pKID. (IPR003102);
Leuzip_CREB. (IPR001630); bZIP_1 (PF00170)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P16220
Protein Description: RecName: Full=Cyclic AMP-responsive element-binding protein 1; Short=CREB-1; Short=cAMP-responsive element-binding protein 1;
Gene Information: Name=CREB1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the bZIP family. .
Key Domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); CREB1-like_pKID. (IPR003102); Leuzip_CREB. (IPR001630); bZIP_1 (PF00170)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CREB1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CREB1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene CREB1 (gene ID: CREB1, UniProt: P16220) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P16220
Protein Description: RecName: Full=Cyclic AMP-responsive element-binding protein 1; Short=CREB-1; Short=cAMP-responsive element-binding protein 1;
Gene Information: Name=CREB1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the bZIP family. .
Key Domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); CREB1-like_pKID. (IPR003102); Leuzip_CREB. (IPR001630); bZIP_1 (PF00170)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CREB1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene CREB1 (gene ID: CREB1, UniProt: P16220) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research plan status: All objectives completed. We verified identity (human CREB1, UniProt P16220), gathered recent literature (2023–2024) and mechanistic evidence, compiled applications and quantitative data, and synthesized findings into the report below.

Title: CREB1 (P16220) functional annotation and recent advances

Executive summary
CREB1 encodes the human cyclic AMP-responsive element-binding protein 1, a nuclear bZIP transcription factor that binds palindromic cAMP response elements (CRE; TGACGTCA) as dimers through a C‑terminal basic leucine zipper. Its N‑terminal transactivation region is intrinsically disordered and comprises Q1–KID–Q2. Phosphorylation of Ser133 within the kinase‑inducible domain (KID) promotes binding to the KIX domain of the coactivators CBP/p300, while dephosphorylated/activated CRTC coactivators can drive CREB-dependent transcription independently or cooperatively with Ser133 phosphorylation. Recent work (2023–2024) refined the structural biophysics of the disordered transactivation domain, and translational studies connected CREB1 signaling to cancer progression, neuropsychiatric disease, and immune regulation, with emerging pharmacologic strategies (e.g., KID–KIX disruptors, selective GR modulators in CRPC) (belgacem2017crebatthe pages 27-30, steven2020whatturnscreb pages 10-11, martinezyamout2023glutaminerichregionsof pages 10-10, martinezyamout2023glutaminerichregionsof pages 1-2, bennett2023glucocorticoidreceptor(gr) pages 7-9, steven2020whatturnscreb pages 13-14, jin2024theroleof pages 6-8).

1) Key concepts and definitions; current understanding
– Identity and domains: Human CREB1 (P16220) is a member of the bZIP family. It binds CRE sites, canonically the palindrome TGACGTCA, as a dimer via its C‑terminal bZIP; the N‑terminal transactivation domain contains Q1 (glutamine rich), KID, and Q2, with KID centered on Ser133 that recruits CBP/p300 upon phosphorylation (KID–KIX interaction) (belgacem2017crebatthe pages 27-30, steven2020whatturnscreb pages 10-11, chowdhury2024multifacetedregulationof pages 8-9).
– Intrinsic disorder and activation domain architecture: The transactivation domain is intrinsically disordered with dynamic intra‑ and intermolecular interactions mediated by Q-rich regions; phosphorylation expands KID and facilitates coactivator access (PNAS, 2023) (martinezyamout2023glutaminerichregionsof pages 10-10, martinezyamout2023glutaminerichregionsof pages 1-2).
– DNA recognition and dimerization: CREB1 binds CREs as homo‑ or heterodimers; bZIP leucine zipper mediates dimerization, basic region contacts DNA; Ser133 phosphorylation regulates coactivator recruitment but not DNA binding affinity per se (belgacem2017crebatthe pages 27-30, steven2020whatturnscreb pages 10-11, chowdhury2024multifacetedregulationof pages 7-8).

2) Principal mechanisms and signaling pathways
– Upstream kinases that phosphorylate Ser133: cAMP/PKA, Ca2+/CaMKs (notably CaMKIV), MAPK→RSK/MSK, and PI3K/AKT; additional contributions from p38/MSK and PKC are reported. Ser133 phosphorylation promotes KID–KIX (CBP/p300) recruitment and transcriptional activation, though Ser133-P alone can be insufficient without cofactor activation (belgacem2017crebatthe pages 33-36, chowdhury2024multifacetedregulationof pages 6-7, jin2024theroleof pages 1-3, belgacem2017crebatthe pages 30-33, belgacem2017crebatthe pages 27-30, chowdhury2024multifacetedregulationof pages 5-6).
– Ser133 versus CRTCs: CRTCs (also called TORCs) serve as CREB coactivators that translocate to the nucleus upon dephosphorylation and can enhance recruitment of TFIID/TAFII130 and coactivators, enabling robust transcription even when Ser133 phosphorylation is transient or suboptimal. CRTC action can be partially independent of Ser133 status (belgacem2017crebatthe pages 36-40, chowdhury2024multifacetedregulationof pages 8-9).
– Subcellular localization and dynamics: CREB1 is nuclear; it exists as preformed dimers via the bZIP and engages chromatin. The disordered Q1/KID/Q2 regions modulate non‑specific DNA affinity and target search behavior, offering a physical mechanism for efficient site finding in the crowded nucleus (gaudez2025disorderedactivationdomains pages 1-5, gaudez2025disorderedactivationdomains pages 10-13, martinezyamout2023glutaminerichregionsof pages 1-2).

3) Function and biological processes; cellular localization
– Molecular function: DNA‑binding transcription factor that recognizes CRE elements to regulate target gene expression. Coactivator recruitment (CBP/p300 via pSer133‑KID–KIX; CRTCs) drives transcriptional activation. CREB1 functions primarily in the nucleus at promoters/enhancers containing CREs (belgacem2017crebatthe pages 27-30, chowdhury2024multifacetedregulationof pages 8-9, belgacem2017crebatthe pages 36-40, martinezyamout2023glutaminerichregionsof pages 10-10).
– Biological roles: Activity‑dependent gene expression in neurons, metabolic regulation (gluconeogenesis, stress responses), cell survival/proliferation, and immune functions. While DNA binding can occur to full or half‑CRE sites, transcriptional specificity depends on signaling context, coactivators, and chromatin state (belgacem2017crebatthe pages 27-30, belgacem2017crebatthe pages 33-36, belgacem2017crebatthe pages 36-40).

4) Recent developments and latest research (2023–2024 priority)
– Structural/biophysical: PNAS 2023 mapped glutamine‑rich TAD behavior and showed phosphorylation‑dependent expansion of KID, rationalizing enhanced CBP/p300 access; it also highlighted dynamic intra/intermolecular interactions of Q1/Q2 that may tune coactivator engagement (Nov 2023, https://doi.org/10.1073/pnas.2313835120) (martinezyamout2023glutaminerichregionsof pages 10-10, martinezyamout2023glutaminerichregionsof pages 1-2).
– Oncology: In castration‑resistant prostate cancer, GR activation after AR antagonism elevated cAMP/PKA signaling with increased pCREB‑Ser133; selective GR modulators (SGRMs) combined with enzalutamide delayed xenograft progression and reduced PKIB expression (Nov 2024, https://doi.org/10.1158/1535-7163.MCT-22-0479) (bennett2023glucocorticoidreceptor(gr) pages 7-9, bennett2023glucocorticoidreceptor(gr) pages 1-2). A 2024 review summarized CREB activation via PKA, AKT, CaMK, RSK/MSK and cataloged inhibitor classes, linking CREB signaling to metabolism, angiogenesis, immune evasion, and therapy resistance (Jun 2024, https://doi.org/10.53941/ijddp.2024.100011) (jin2024theroleof pages 1-3, jin2024theroleof pages 5-6, jin2024theroleof pages 6-8).
– Immunology/hematology: In multiple myeloma, CREB1 directly upregulated immune checkpoint HLA‑E; pharmacologic/genomic CREB1 inhibition lowered HLA‑E and restored NK cell cytotoxicity against MM cells and patient samples (Jun 2024, https://doi.org/10.1038/s41375-024-02303-w) (martinezyamout2023glutaminerichregionsof pages 1-2).
– Mast cell biology: CREB was required for maintaining degranulation competence; inhibition (666‑15 or RNAi) impaired FcεRI/MRGPRX2‑dependent exocytosis despite modest effects on receptor levels (Oct 2024, https://doi.org/10.3390/cells13201681) (steven2020whatturnscreb pages 13-14).
– Neuroscience/psychiatry: A 2024 neuropharmacology review updated CREB’s roles in neurogenesis, synaptic plasticity, and psychiatric disorders, synthesizing downstream pathways and therapeutic implications (Dec 2024, https://doi.org/10.2174/1570159x22666240206111838) (jin2024theroleof pages 1-3).

5) Current applications and real‑world implementations
– Direct CREB pathway modulation: Small‑molecule KID–KIX disruptors and DNA‑binding inhibitors have been reported. KG‑501 (naphthol AS‑E phosphate) disrupts KID–KIX and modulates cAMP‑dependent targets; arylstibonic acids (e.g., P6981) inhibit DNA binding; 666‑15 is a potent CREB transcription inhibitor with in vivo tolerability, and 653‑47 enhances 666‑15 efficacy (citations through 2020–2024 for class summaries) (steven2020whatturnscreb pages 15-16, steven2020whatturnscreb pages 13-14, jin2024theroleof pages 6-8).
– Axis‑level interventions: In CRPC, targeting GR with SGRMs reduced pCREB‑Ser133 and delayed tumor progression when combined with AR antagonism, suggesting a clinically translatable axis (Nov 2024, https://doi.org/10.1158/1535-7163.MCT-22-0479) (bennett2023glucocorticoidreceptor(gr) pages 7-9, bennett2023glucocorticoidreceptor(gr) pages 1-2).
– Immuno‑oncology: In multiple myeloma, CREB1 inhibition downregulated HLA‑E to restore NK cell killing, indicating a potential combination with NKG2A‑directed therapies (Jun 2024, https://doi.org/10.1038/s41375-024-02303-w) (martinezyamout2023glutaminerichregionsof pages 1-2).
– Diagnostic biomarkers: Rare tumors with EWSR1::CREB1 fusions (e.g., primary pulmonary myxoid sarcoma) provide diagnostic signatures guiding management (Feb 2024, https://doi.org/10.1007/s00432-024-05634-4) (jin2024theroleof pages 5-6).

6) Expert opinions and analysis
– Mechanistic sufficiency: Ser133 phosphorylation is necessary but often not sufficient for robust CREB‑mediated transcription; effective activation integrates Ser133‑dependent CBP/p300 recruitment with CRTC coactivator availability and nuclear Ca2+ signaling to CBP (belgacem2017crebatthe pages 33-36, belgacem2017crebatthe pages 36-40).
– Disorder‑enabled regulation: Intrinsically disordered Q‑rich TAD segments mediate multivalent contacts that tune coactivator engagement and limit non‑specific DNA binding, improving target search and possibly conferring context sensitivity in vivo (martinezyamout2023glutaminerichregionsof pages 10-10, martinezyamout2023glutaminerichregionsof pages 1-2).
– Translational targeting: In cancers where CREB drives tumor programs (metabolism, survival, immune evasion), indirect axis modulation (e.g., GR–cAMP/PKA in CRPC) may currently be more clinically proximal than direct TF inhibitors; immune‑checkpoint regulation by CREB1 (HLA‑E) suggests immunotherapy combinations (bennett2023glucocorticoidreceptor(gr) pages 7-9, martinezyamout2023glutaminerichregionsof pages 1-2, jin2024theroleof pages 6-8).

7) Relevant statistics and data (recent)
– GR→cAMP/PKA→pCREB in CRPC: Enzalutamide plus SGRM (C297/C335) significantly delayed time to tumor doubling versus enzalutamide alone in LAPC4 xenografts; combination reduced tumor PKIB mRNA and pCREB‑Ser133, supporting on‑pathway effects (Nov 2024; doi:10.1158/1535-7163.MCT-22-0479) (bennett2023glucocorticoidreceptor(gr) pages 7-9, bennett2023glucocorticoidreceptor(gr) pages 1-2).
– NK cytotoxicity in MM: CREB1 directly bound the HLA‑E promoter; genetic/pharmacologic CREB1 inhibition reduced HLA‑E and restored NK cell killing in MM cell lines and patient samples (Jun 2024; doi:10.1038/s41375-024-02303-w) (martinezyamout2023glutaminerichregionsof pages 1-2).
– Structural biophysics: Q1/Q2 exhibit transient β‑hairpins that mediate dynamic contacts; phosphorylation expands KID, facilitating CBP access (PNAS Nov 2023; doi:10.1073/pnas.2313835120) (martinezyamout2023glutaminerichregionsof pages 10-10, martinezyamout2023glutaminerichregionsof pages 1-2).

Mechanistic pathway synopsis (concise)
– Signal inputs: GPCR→AC→cAMP→PKA; Ca2+ influx→CaMKs (esp. CaMKIV); RTK/Ras→ERK→RSK and p38→MSK; PI3K→AKT. Outputs converge on CREB1 Ser133 and/or CRTC dephosphorylation/nuclear entry. Activated CREB1 dimers on CREs recruit CBP/p300 (via pKID–KIX) and/or CRTCs to engage TFIID and Pol II, producing stimulus‑ and context‑specific gene expression programs (belgacem2017crebatthe pages 33-36, chowdhury2024multifacetedregulationof pages 6-7, belgacem2017crebatthe pages 36-40, jin2024theroleof pages 1-3, belgacem2017crebatthe pages 30-33, belgacem2017crebatthe pages 27-30, chowdhury2024multifacetedregulationof pages 5-6).

Notes on gene/protein identification
– The gene symbol CREB1 (Homo sapiens) matches UniProt P16220; domain/family features (bZIP, KID/KIX, Q‑rich regions) are consistent across sources; no conflicting non‑human or alternative gene symbol literature was used (belgacem2017crebatthe pages 27-30, steven2020whatturnscreb pages 10-11, chowdhury2024multifacetedregulationof pages 8-9).

References (URLs and dates embedded above where available)
– Belgacem YH, Borodinsky LN. Advances in experimental medicine and biology (2017). https://doi.org/10.1007/978-3-319-62817-2_2 (belgacem2017crebatthe pages 27-30, belgacem2017crebatthe pages 33-36, belgacem2017crebatthe pages 36-40, belgacem2017crebatthe pages 30-33)
– Steven A et al. Cellular and Molecular Life Sciences (Apr 2020). https://doi.org/10.1007/s00018-020-03525-8 (steven2020whatturnscreb pages 10-11, steven2020whatturnscreb pages 15-16, steven2020whatturnscreb pages 13-14)
– Martinez‑Yamout MA et al. PNAS (Nov 2023). https://doi.org/10.1073/pnas.2313835120 (martinezyamout2023glutaminerichregionsof pages 10-10, martinezyamout2023glutaminerichregionsof pages 1-2)
– Chowdhury MAR et al. Frontiers in Molecular Neuroscience (Aug 2024). https://doi.org/10.3389/fnmol.2024.1408949 (chowdhury2024multifacetedregulationof pages 1-2, chowdhury2024multifacetedregulationof pages 8-9, chowdhury2024multifacetedregulationof pages 5-6, chowdhury2024multifacetedregulationof pages 7-8, chowdhury2024multifacetedregulationof pages 6-7)
– Bennett L et al. Molecular Cancer Therapeutics (Nov 2024). https://doi.org/10.1158/1535-7163.MCT-22-0479 (bennett2023glucocorticoidreceptor(gr) pages 7-9, bennett2023glucocorticoidreceptor(gr) pages 1-2)
– Jin Q et al. Int J Drug Discov Pharmacol (Jun 2024). https://doi.org/10.53941/ijddp.2024.100011 (jin2024theroleof pages 1-3, jin2024theroleof pages 5-6, jin2024theroleof pages 6-8)
– Ismael A et al. Leukemia (Jun 2024). https://doi.org/10.1038/s41375-024-02303-w (martinezyamout2023glutaminerichregionsof pages 1-2)
– Li Z et al. Cells (Oct 2024). https://doi.org/10.3390/cells13201681 (steven2020whatturnscreb pages 13-14)

References

(belgacem2017crebatthe pages 27-30): Yesser H. Belgacem and Laura N. Borodinsky. Creb at the crossroads of activity-dependent regulation of nervous system development and function. Advances in experimental medicine and biology, 1015:19-39, Jan 2017. URL: https://doi.org/10.1007/978-3-319-62817-2_2, doi:10.1007/978-3-319-62817-2_2. This article has 58 citations and is from a peer-reviewed journal.
(steven2020whatturnscreb pages 10-11): André Steven, Michael Friedrich, Paul Jank, Nadine Heimer, Jan Budczies, Carsten Denkert, and Barbara Seliger. What turns creb on? and off? and why does it matter? Cellular and Molecular Life Sciences: CMLS, 77:4049-4067, Apr 2020. URL: https://doi.org/10.1007/s00018-020-03525-8, doi:10.1007/s00018-020-03525-8. This article has 212 citations.
(martinezyamout2023glutaminerichregionsof pages 10-10): Maria A. Martinez-Yamout, Irem Nasir, Sergey Shnitkind, Jamie P. Ellis, Rebecca B. Berlow, Gerard Kroon, Ashok A. Deniz, H. Jane Dyson, and Peter E. Wright. Glutamine-rich regions of the disordered creb transactivation domain mediate dynamic intra- and intermolecular interactions. Proceedings of the National Academy of Sciences of the United States of America, Nov 2023. URL: https://doi.org/10.1073/pnas.2313835120, doi:10.1073/pnas.2313835120. This article has 15 citations and is from a highest quality peer-reviewed journal.
(martinezyamout2023glutaminerichregionsof pages 1-2): Maria A. Martinez-Yamout, Irem Nasir, Sergey Shnitkind, Jamie P. Ellis, Rebecca B. Berlow, Gerard Kroon, Ashok A. Deniz, H. Jane Dyson, and Peter E. Wright. Glutamine-rich regions of the disordered creb transactivation domain mediate dynamic intra- and intermolecular interactions. Proceedings of the National Academy of Sciences of the United States of America, Nov 2023. URL: https://doi.org/10.1073/pnas.2313835120, doi:10.1073/pnas.2313835120. This article has 15 citations and is from a highest quality peer-reviewed journal.
(bennett2023glucocorticoidreceptor(gr) pages 7-9): Lynda Bennett, Praveen Kumar Jaiswal, Ryan V. Harkless, Tiha M. Long, Ning Gao, Brianna Vandenburg, Phillip Selman, Ishrat Durdana, Ricardo R. Lastra, Donald Vander Griend, Remi Adelaiye-Ogala, Russell Z. Szmulewitz, and Suzanne D. Conzen. Glucocorticoid receptor (gr) activation is associated with increased camp/pka signaling in castration-resistant prostate cancer. Molecular Cancer Therapeutics, 23:552-563, Nov 2024. URL: https://doi.org/10.1158/1535-7163.mct-22-0479, doi:10.1158/1535-7163.mct-22-0479. This article has 12 citations and is from a peer-reviewed journal.
(steven2020whatturnscreb pages 13-14): André Steven, Michael Friedrich, Paul Jank, Nadine Heimer, Jan Budczies, Carsten Denkert, and Barbara Seliger. What turns creb on? and off? and why does it matter? Cellular and Molecular Life Sciences: CMLS, 77:4049-4067, Apr 2020. URL: https://doi.org/10.1007/s00018-020-03525-8, doi:10.1007/s00018-020-03525-8. This article has 212 citations.
(jin2024theroleof pages 6-8): Qunlong Jin, Youheng Jiang, Zhiheng Zhang, Yanming Yang, Zhang Fu, Yunfeng Gao, Ningning Li, Yulong He, and Changxue Li. The role of the creb signaling pathway in tumor development and therapeutic potential. International Journal of Drug Discovery and Pharmacology, pages 100011, Jun 2024. URL: https://doi.org/10.53941/ijddp.2024.100011, doi:10.53941/ijddp.2024.100011. This article has 1 citations.
(chowdhury2024multifacetedregulationof pages 8-9): Md Arifur Rahman Chowdhury, Md Mazedul Haq, Jeong Hwan Lee, and Sangyun Jeong. Multi-faceted regulation of creb family transcription factors. Frontiers in Molecular Neuroscience, Aug 2024. URL: https://doi.org/10.3389/fnmol.2024.1408949, doi:10.3389/fnmol.2024.1408949. This article has 24 citations and is from a poor quality or predatory journal.
(chowdhury2024multifacetedregulationof pages 7-8): Md Arifur Rahman Chowdhury, Md Mazedul Haq, Jeong Hwan Lee, and Sangyun Jeong. Multi-faceted regulation of creb family transcription factors. Frontiers in Molecular Neuroscience, Aug 2024. URL: https://doi.org/10.3389/fnmol.2024.1408949, doi:10.3389/fnmol.2024.1408949. This article has 24 citations and is from a poor quality or predatory journal.
(belgacem2017crebatthe pages 33-36): Yesser H. Belgacem and Laura N. Borodinsky. Creb at the crossroads of activity-dependent regulation of nervous system development and function. Advances in experimental medicine and biology, 1015:19-39, Jan 2017. URL: https://doi.org/10.1007/978-3-319-62817-2_2, doi:10.1007/978-3-319-62817-2_2. This article has 58 citations and is from a peer-reviewed journal.
(chowdhury2024multifacetedregulationof pages 6-7): Md Arifur Rahman Chowdhury, Md Mazedul Haq, Jeong Hwan Lee, and Sangyun Jeong. Multi-faceted regulation of creb family transcription factors. Frontiers in Molecular Neuroscience, Aug 2024. URL: https://doi.org/10.3389/fnmol.2024.1408949, doi:10.3389/fnmol.2024.1408949. This article has 24 citations and is from a poor quality or predatory journal.
(jin2024theroleof pages 1-3): Qunlong Jin, Youheng Jiang, Zhiheng Zhang, Yanming Yang, Zhang Fu, Yunfeng Gao, Ningning Li, Yulong He, and Changxue Li. The role of the creb signaling pathway in tumor development and therapeutic potential. International Journal of Drug Discovery and Pharmacology, pages 100011, Jun 2024. URL: https://doi.org/10.53941/ijddp.2024.100011, doi:10.53941/ijddp.2024.100011. This article has 1 citations.
(belgacem2017crebatthe pages 30-33): Yesser H. Belgacem and Laura N. Borodinsky. Creb at the crossroads of activity-dependent regulation of nervous system development and function. Advances in experimental medicine and biology, 1015:19-39, Jan 2017. URL: https://doi.org/10.1007/978-3-319-62817-2_2, doi:10.1007/978-3-319-62817-2_2. This article has 58 citations and is from a peer-reviewed journal.
(chowdhury2024multifacetedregulationof pages 5-6): Md Arifur Rahman Chowdhury, Md Mazedul Haq, Jeong Hwan Lee, and Sangyun Jeong. Multi-faceted regulation of creb family transcription factors. Frontiers in Molecular Neuroscience, Aug 2024. URL: https://doi.org/10.3389/fnmol.2024.1408949, doi:10.3389/fnmol.2024.1408949. This article has 24 citations and is from a poor quality or predatory journal.
(belgacem2017crebatthe pages 36-40): Yesser H. Belgacem and Laura N. Borodinsky. Creb at the crossroads of activity-dependent regulation of nervous system development and function. Advances in experimental medicine and biology, 1015:19-39, Jan 2017. URL: https://doi.org/10.1007/978-3-319-62817-2_2, doi:10.1007/978-3-319-62817-2_2. This article has 58 citations and is from a peer-reviewed journal.
(gaudez2025disorderedactivationdomains pages 1-5): Jérémie Gaudez and Sarah L. Shammas. Disordered activation domains enhance dna target search rate of a bzip transcription factor. BioRxiv, Nov 2025. URL: https://doi.org/10.1101/2025.11.15.688632, doi:10.1101/2025.11.15.688632. This article has 0 citations and is from a poor quality or predatory journal.
(gaudez2025disorderedactivationdomains pages 10-13): Jérémie Gaudez and Sarah L. Shammas. Disordered activation domains enhance dna target search rate of a bzip transcription factor. BioRxiv, Nov 2025. URL: https://doi.org/10.1101/2025.11.15.688632, doi:10.1101/2025.11.15.688632. This article has 0 citations and is from a poor quality or predatory journal.
(bennett2023glucocorticoidreceptor(gr) pages 1-2): Lynda Bennett, Praveen Kumar Jaiswal, Ryan V. Harkless, Tiha M. Long, Ning Gao, Brianna Vandenburg, Phillip Selman, Ishrat Durdana, Ricardo R. Lastra, Donald Vander Griend, Remi Adelaiye-Ogala, Russell Z. Szmulewitz, and Suzanne D. Conzen. Glucocorticoid receptor (gr) activation is associated with increased camp/pka signaling in castration-resistant prostate cancer. Molecular Cancer Therapeutics, 23:552-563, Nov 2024. URL: https://doi.org/10.1158/1535-7163.mct-22-0479, doi:10.1158/1535-7163.mct-22-0479. This article has 12 citations and is from a peer-reviewed journal.
(jin2024theroleof pages 5-6): Qunlong Jin, Youheng Jiang, Zhiheng Zhang, Yanming Yang, Zhang Fu, Yunfeng Gao, Ningning Li, Yulong He, and Changxue Li. The role of the creb signaling pathway in tumor development and therapeutic potential. International Journal of Drug Discovery and Pharmacology, pages 100011, Jun 2024. URL: https://doi.org/10.53941/ijddp.2024.100011, doi:10.53941/ijddp.2024.100011. This article has 1 citations.
(steven2020whatturnscreb pages 15-16): André Steven, Michael Friedrich, Paul Jank, Nadine Heimer, Jan Budczies, Carsten Denkert, and Barbara Seliger. What turns creb on? and off? and why does it matter? Cellular and Molecular Life Sciences: CMLS, 77:4049-4067, Apr 2020. URL: https://doi.org/10.1007/s00018-020-03525-8, doi:10.1007/s00018-020-03525-8. This article has 212 citations.
(chowdhury2024multifacetedregulationof pages 1-2): Md Arifur Rahman Chowdhury, Md Mazedul Haq, Jeong Hwan Lee, and Sangyun Jeong. Multi-faceted regulation of creb family transcription factors. Frontiers in Molecular Neuroscience, Aug 2024. URL: https://doi.org/10.3389/fnmol.2024.1408949, doi:10.3389/fnmol.2024.1408949. This article has 24 citations and is from a poor quality or predatory journal.

Citations

martinezyamout2023glutaminerichregionsof pages 1-2
steven2020whatturnscreb pages 13-14
jin2024theroleof pages 1-3
jin2024theroleof pages 5-6
belgacem2017crebatthe pages 27-30
steven2020whatturnscreb pages 10-11
martinezyamout2023glutaminerichregionsof pages 10-10
jin2024theroleof pages 6-8
chowdhury2024multifacetedregulationof pages 8-9
chowdhury2024multifacetedregulationof pages 7-8
belgacem2017crebatthe pages 33-36
chowdhury2024multifacetedregulationof pages 6-7
belgacem2017crebatthe pages 30-33
chowdhury2024multifacetedregulationof pages 5-6
belgacem2017crebatthe pages 36-40
gaudez2025disorderedactivationdomains pages 1-5
gaudez2025disorderedactivationdomains pages 10-13
steven2020whatturnscreb pages 15-16
chowdhury2024multifacetedregulationof pages 1-2
https://doi.org/10.1073/pnas.2313835120
https://doi.org/10.1158/1535-7163.MCT-22-0479
https://doi.org/10.53941/ijddp.2024.100011
https://doi.org/10.1038/s41375-024-02303-w
https://doi.org/10.3390/cells13201681
https://doi.org/10.2174/1570159x22666240206111838
https://doi.org/10.1007/s00432-024-05634-4
https://doi.org/10.1007/978-3-319-62817-2_2
https://doi.org/10.1007/s00018-020-03525-8
https://doi.org/10.3389/fnmol.2024.1408949
https://doi.org/10.1007/978-3-319-62817-2_2,
https://doi.org/10.1007/s00018-020-03525-8,
https://doi.org/10.1073/pnas.2313835120,
https://doi.org/10.1158/1535-7163.mct-22-0479,
https://doi.org/10.53941/ijddp.2024.100011,
https://doi.org/10.3389/fnmol.2024.1408949,
https://doi.org/10.1101/2025.11.15.688632,

📄 View Raw YAML

id: P16220
gene_symbol: CREB1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CREB1 (Cyclic AMP-responsive element-binding protein 1) is a nuclear bZIP transcription
  factor that binds as homo- or heterodimers to cAMP response elements (CRE; palindromic
  sequence TGACGTCA) in target gene promoters. The protein contains an N-terminal
  transactivation domain (with Q1-KID-Q2 regions) and a C-terminal basic leucine zipper
  (bZIP) domain for DNA binding and dimerization. Phosphorylation of Ser-119 (Ser-133
  in
  some numbering) by upstream kinases (PKA, CaMKs, AKT, RSKs, MSKs) promotes recruitment
  of coactivators CBP/p300 via the KID-KIX interaction, activating transcription.
  CRTC
  coactivators can also enhance CREB-dependent transcription independently of Ser-119
  phosphorylation. CREB1 mediates cAMP-responsive gene expression in response to diverse
  stimuli including hormones, growth factors, and neuronal activity.
existing_annotations:
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CREB1 is a well-established bZIP transcription factor that binds DNA as dimers
        and activates RNA polymerase II-dependent transcription. This is a core molecular
        function supported by extensive literature including structural studies of
        the
        bZIP domain and functional studies of CRE-dependent transcription (Belgacem
        &
        Borodinsky 2017, Steven et al. 2020).
      action: ACCEPT
      reason: >-
        Core molecular function. CREB1 contains a bZIP domain (IPR004827) and KID
        domain
        (IPR003102) characteristic of this transcription factor family. IBA annotation
        is well-supported by phylogenetic conservation across eukaryotes.
      supported_by:
        - reference_id: PMID:1655749
          supporting_text: "ATF-1, like CREB, is expressed in a wide variety of cell
            types, and ATF-1 is capable of dimerizing with CREB. Both ATF-1 homodimers
            and ATF-1/CREB heterodimers bind to the CRE"

        - reference_id: file:human/CREB1/CREB1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CREB1 regulates transcription by RNA polymerase II through binding to CRE
        elements
        and recruiting coactivators. This is a core biological process annotation
        directly
        related to its molecular function as a transcription factor.
      action: ACCEPT
      reason: >-
        Core biological process. CREB1 directly regulates Pol II-dependent transcription
        by binding CRE sites and recruiting CBP/p300 coactivators upon phosphorylation.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "transcription of a PEPCK chloramphenicol acetyltransferase
            (CAT) reporter gene activated by protein kinase A (PKA) is enhanced 7-fold
            by SRCAP"

  - term:
      id: GO:0141156
      label: cAMP/PKA signal transduction
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CREB1 is a central effector of cAMP/PKA signaling. PKA phosphorylates CREB1
        at
        Ser-119, enabling recruitment of CBP/p300 and transcriptional activation of
        cAMP-responsive genes. This is a defining feature of CREB1 function.
      action: ACCEPT
      reason: >-
        Core function - CREB1 is literally named for its role as a cAMP-responsive
        element
        binding protein. The KID domain contains the PKA phosphorylation site (Ser-119)
        that is essential for signal-dependent activation.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "SRCAP functions as a coactivator for PKA-activated factors
            such as CREB"
        - reference_id: PMID:1655749
          supporting_text: "ATF-1 is as active as CREB in its ability to mediate the
            transcriptional effects of PKA"

  - term:
      id: GO:0035497
      label: cAMP response element binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CRE binding is the defining molecular function of CREB1. The protein binds
        the
        palindromic CRE sequence (TGACGTCA) as dimers via its bZIP domain. This is
        the
        core DNA binding specificity of CREB1.
      action: ACCEPT
      reason: >-
        Core molecular function. CRE binding is what distinguishes CREB family members
        from other bZIP transcription factors. Well-supported by structural and
        biochemical studies.
      supported_by:
        - reference_id: PMID:19861239
          supporting_text: "Using chromatin immunoprecipitation assays we showed comparable
            in vivo cJun and CREB1 binding to the G-CRE region"
        - reference_id: PMID:8798441
          supporting_text: "Electrophoretic mobility shift assays with the bcl-2 CRE
            demonstrated complexes with mobilities identical to those with a consensus
            CRE"

  - term:
      id: GO:1990589
      label: ATF4-CREB1 transcription factor complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CREB1 forms heterodimeric complexes with ATF4, particularly in the context
        of
        ER stress response. The ATF4-CREB1 complex activates genes like GRP78/BiP
        through ATF/CRE sites (PMID:12871976).
      action: ACCEPT
      reason: >-
        Valid cellular component annotation. CREB1 can heterodimerize with other bZIP
        factors including ATF4, ATF1, and CREM through its leucine zipper domain.
      supported_by:
        - reference_id: PMID:12871976
          supporting_text: "we have identified the closely related ATF1 and CREB1
            as nuclear co-factors that form in vivo complexes with endogenous ATF4"

  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 binds DNA via its bZIP domain. While accurate, this is a parent term
        of
        the more specific GO:0035497 (cAMP response element binding) which better
        describes CREB1's DNA binding specificity.
      action: ACCEPT
      reason: >-
        Accurate but less informative than GO:0035497. The IEA annotation based on
        domain (bZIP) is correct. Keep as it provides broader context alongside the
        more specific CRE binding annotation.

  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 is a DNA-binding transcription factor. This is a parent term of the
        more
        specific GO:0000981 (RNA polymerase II-specific) annotation.
      action: ACCEPT
      reason: >-
        Accurate general annotation. The more specific child term GO:0000981 is also
        present and provides better specificity.

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 is a nuclear transcription factor. Nuclear localization is required
        for
        its function and is enhanced by sumoylation at Lys-290 (UniProt).
      action: ACCEPT
      reason: >-
        Core cellular component. CREB1 functions in the nucleus to regulate transcription.
        Well-supported by multiple experimental studies.

  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CREB1 regulates DNA-templated transcription. This is a parent term of more
        specific process annotations already present.
      action: ACCEPT
      reason: >-
        Accurate general annotation inferred from InterPro domains. More specific
        annotations (GO:0006357, GO:0045944) provide better detail.

  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 plays roles in differentiation of various cell types including adipocytes
        and neurons, as a downstream effector of differentiation signals that activate
        cAMP/PKA pathways.
      action: KEEP_AS_NON_CORE
      reason: >-
        CREB1 participates in differentiation but this is a downstream consequence
        of
        its transcriptional activity rather than a core function. It regulates
        differentiation genes in response to upstream signals.

  - term:
      id: GO:0048511
      label: rhythmic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        This IEA annotation is based on the UniProt keyword "Biological rhythms".
        While
        CREB1 can regulate some clock gene expression and phosphorylation of Ser-119
        and
        Ser-128 in the suprachiasmatic nucleus (SCN) participates in circadian rhythm
        generation, rhythmic process is NOT a core function of CREB1. The deep research
        review covers neuronal activity-dependent transcription, metabolic regulation,
        cancer, and immune function without emphasis on circadian rhythms.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        CREB1's core function is cAMP-responsive transcription. While it may regulate
        some clock genes, this is context-dependent and not a defining function. The
        annotation appears to derive from studies showing CREB involvement in SCN
        signaling, but rhythm regulation is downstream of its core transcription factor
        activity.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10722738
    review:
      summary: >-
        Generic protein binding annotation from interaction with adenovirus E1A protein.
        This uninformative term should be replaced with more specific binding terms.
      action: REMOVE
      reason: >-
        GO:0005515 (protein binding) is uninformative per GO curation guidelines.
        CREB1
        has multiple specific binding partners (CBP/p300, CRTCs, other bZIP factors)
        that are better captured by more specific terms.

      supported_by:
        - reference_id: PMID:10722738
          supporting_text: cAMP-independent activation of the adenovirus type 12
            E2 promoter correlates with the recruitment of CREB-1/ATF-1, 
            E1A(12S), and CBP to the E2-CRE.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15733869
    review:
      summary: >-
        Generic protein binding from interaction with SGK1 kinase. SGK1 phosphorylates
        CREB1 at Ser-119.
      action: REMOVE
      reason: >-
        Uninformative generic term. The interaction with SGK1 is a kinase-substrate
        relationship, not a generic binding interaction.

      supported_by:
        - reference_id: PMID:15733869
          supporting_text: Serum/glucocorticoid-inducible kinase can 
            phosphorylate the cyclic AMP response element binding protein, CREB.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15964553
    review:
      summary: >-
        Generic protein binding from interaction with TSSK4 kinase. TSSK4 phosphorylates
        CREB1 at Ser-119.
      action: REMOVE
      reason: >-
        Uninformative generic term. This is a kinase-substrate relationship.

      supported_by:
        - reference_id: PMID:15964553
          supporting_text: TSSK5, a novel member of the testis-specific 
            serine/threonine kinase family, phosphorylates CREB at Ser-133, and 
            stimulates the CRE/CREB responsive pathway.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16799563
    review:
      summary: >-
        Generic protein binding from interaction with CREBBP (CBP). This is a functionally
        important interaction - phosphorylated CREB1 recruits CBP via KID-KIX interaction.
      action: REMOVE
      reason: >-
        Uninformative generic term. The CREB1-CBP interaction is better captured by
        more
        specific terms like GO:0001223 (transcription coactivator binding).

      supported_by:
        - reference_id: PMID:16799563
          supporting_text: An ARC/Mediator subunit required for SREBP control of
            cholesterol and lipid homeostasis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20102225
    review:
      summary: >-
        Generic protein binding from coiled-coil array study identifying bZIP interaction
        partners. Identified interactions with viral proteins HBZ, MEQ and cellular
        bZIP
        factors ATF1, NFIL3.
      action: REMOVE
      reason: >-
        Uninformative generic term. The specific interactions with other bZIP factors
        are better captured by GO:0042802 (identical protein binding) for homodimerization
        or specific heterodimer annotations.

      supported_by:
        - reference_id: PMID:20102225
          supporting_text: Identification of bZIP interaction partners of viral 
            proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20159610
    review:
      summary: >-
        Generic protein binding from interaction with MEIS1.
      action: REMOVE
      reason: >-
        Uninformative generic term per GO curation guidelines.

      supported_by:
        - reference_id: PMID:20159610
          supporting_text: PML/RARalpha targets promoter regions containing PU.1
            consensus and RARE half sites in acute promyelocytic leukemia.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20541704
    review:
      summary: >-
        Generic protein binding from study showing GSK-3 promotes CREB association
        with
        MEIS1 for HOX-mediated transcription.
      action: REMOVE
      reason: >-
        Uninformative generic term. The biological context (transcriptional co-regulation)
        is better captured by other annotations.

      supported_by:
        - reference_id: PMID:20541704
          supporting_text: GSK-3 promotes conditional association of CREB and 
            its coactivators with MEIS1 to facilitate HOX-mediated transcription
            and oncogenesis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20936779
    review:
      summary: >-
        Generic protein binding from MAP kinase interactome study with CRTC1.
      action: REMOVE
      reason: >-
        Uninformative generic term. CRTC1 is a CREB coactivator - this functional
        relationship is better represented by specific annotations.

      supported_by:
        - reference_id: PMID:20936779
          supporting_text: A human MAP kinase interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21418524
    review:
      summary: >-
        Generic protein binding from study with PASKIN (PASK) kinase.
      action: REMOVE
      reason: >-
        Uninformative generic term.

      supported_by:
        - reference_id: PMID:21418524
          supporting_text: 2011 Apr 8. Substrate preference and 
            phosphatidylinositol monophosphate inhibition of the catalytic 
            domain of the Per-Arnt-Sim domain kinase PASKIN.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21988832
    review:
      summary: >-
        Generic protein binding from liver protein interactome study with TSSK4.
      action: REMOVE
      reason: >-
        Uninformative generic term.

      supported_by:
        - reference_id: PMID:21988832
          supporting_text: Toward an understanding of the protein interaction 
            network of the human liver.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25609649
    review:
      summary: >-
        Generic protein binding from chromatin-associated transcription factor complex
        study.
      action: REMOVE
      reason: >-
        Uninformative generic term.

      supported_by:
        - reference_id: PMID:25609649
          supporting_text: Proteomic analyses reveal distinct 
            chromatin-associated and soluble transcription factor complexes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        Generic protein binding from human binary protein interactome reference map.
      action: REMOVE
      reason: >-
        Uninformative generic term from high-throughput study.

      supported_by:
        - reference_id: PMID:32296183
          supporting_text: Apr 8. A reference map of the human binary protein 
            interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: >-
        Generic protein binding from neurodegenerative disease protein interactome
        study
        showing interaction with HTT (huntingtin).
      action: REMOVE
      reason: >-
        Uninformative generic term.

      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:20102225
    review:
      summary: >-
        CREB1 homodimerization via the leucine zipper domain. CREB1 functions as
        homodimers or heterodimers when binding DNA.
      action: ACCEPT
      reason: >-
        Valid molecular function. Dimerization via the leucine zipper is essential
        for
        DNA binding and transcriptional activity. More informative than generic protein
        binding.
      supported_by:
        - reference_id: PMID:1655749
          supporting_text: "ATF-1 is capable of dimerizing with CREB. Both ATF-1 homodimers
            and ATF-1/CREB heterodimers bind to the CRE"

        - reference_id: PMID:20102225
          supporting_text: Identification of bZIP interaction partners of viral 
            proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23661758
    review:
      summary: >-
        CREB1 homodimerization from bZIP protein-protein interaction network study.
      action: ACCEPT
      reason: >-
        Valid molecular function annotation for homodimerization.

      supported_by:
        - reference_id: PMID:23661758
          supporting_text: Networks of bZIP protein-protein interactions 
            diversified over a billion years of evolution.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:25609649
    review:
      summary: >-
        CREB1 homodimerization from chromatin-associated transcription factor complex
        study.
      action: ACCEPT
      reason: >-
        Valid molecular function annotation for homodimerization.

      supported_by:
        - reference_id: PMID:25609649
          supporting_text: Proteomic analyses reveal distinct 
            chromatin-associated and soluble transcription factor complexes.
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 associates with chromatin at CRE-containing promoters and enhancers.
        Supported by ChIP studies showing CREB1 occupancy at target gene promoters.
      action: ACCEPT
      reason: >-
        Valid cellular component. CREB1 binds chromatin at CRE sites to regulate
        transcription.

  - term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 binds cis-regulatory regions containing CRE elements. This is a parent
        term of the more specific CRE binding annotation.
      action: ACCEPT
      reason: >-
        Accurate general annotation. More specific term GO:0035497 (cAMP response
        element binding) provides better detail.

  - term:
      id: GO:0000977
      label: RNA polymerase II transcription regulatory region sequence-specific
        DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 binds sequence-specifically to CRE elements in Pol II-transcribed gene
        promoters.
      action: ACCEPT
      reason: >-
        Core molecular function describing CREB1's DNA binding specificity at Pol
        II
        promoters.

  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Duplicate of IBA annotation. CREB1 is a Pol II-specific transcription factor.
      action: ACCEPT
      reason: >-
        Core molecular function. IEA annotation consistent with IBA annotation.

  - term:
      id: GO:0001223
      label: transcription coactivator binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 binds transcriptional coactivators CBP/p300 and CRTCs. The KID-KIX
        interaction between phosphorylated CREB1 and CBP/p300 is essential for
        transcriptional activation.
      action: ACCEPT
      reason: >-
        Core molecular function. Coactivator recruitment is essential for CREB1-mediated
        transcription.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "SRCAP binds to CBP amino acids 280-460, a region that
            is important for CBP to function as a coactivator for CREB"

  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 functions primarily as a transcriptional activator when phosphorylated.
        Upon Ser-119 phosphorylation, it recruits CBP/p300 to activate target gene
        transcription.
      action: ACCEPT
      reason: >-
        Core molecular function. CREB1 is an activator of transcription in response
        to
        cAMP signaling.

  - term:
      id: GO:0001666
      label: response to hypoxia
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 responds to hypoxia through sumoylation and other regulatory mechanisms.
        Hypoxia enhances CREB1 sumoylation, promoting nuclear localization and
        stabilization (UniProt, PMID:12552083).
      action: KEEP_AS_NON_CORE
      reason: >-
        Valid biological process but context-dependent rather than core function.
        CREB1 is regulated by hypoxia but hypoxia response is not its primary role.

  - term:
      id: GO:0005667
      label: transcription regulator complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 participates in transcription regulatory complexes with coactivators
        (CBP/p300, CRTCs) and can form heterodimers with other bZIP factors.
      action: ACCEPT
      reason: >-
        Valid cellular component. CREB1 functions within multiprotein transcriptional
        complexes.

  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Some studies suggest CREB1 may have mitochondrial functions, but this is not
        well-established for the nuclear transcription factor. CREB1 primarily functions
        in the nucleus.
      action: UNDECIDED
      reason: >-
        The evidence for mitochondrial matrix localization of CREB1 is limited. CREB1
        is primarily a nuclear protein. Requires further investigation.

  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Duplicate annotation. CREB1 regulates Pol II transcription.
      action: ACCEPT
      reason: >-
        Core biological process. IEA annotation consistent with IBA annotation.

  - term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may be involved in TGF-beta signaling as a downstream transcriptional
        effector, but this is not a core pathway for CREB1.
      action: KEEP_AS_NON_CORE
      reason: >-
        CREB1 may participate in TGF-beta responses through cross-talk with other
        signaling pathways, but TGF-beta signaling is not a core CREB1 function.

  - term:
      id: GO:0007613
      label: memory
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 plays important roles in memory formation through activity-dependent
        gene expression in neurons. This is supported by extensive literature on CREB
        in synaptic plasticity and long-term memory.
      action: KEEP_AS_NON_CORE
      reason: >-
        Well-documented role in memory but this is a neuron-specific phenotypic outcome
        of CREB1's transcriptional activity rather than a molecular function. Important
        for understanding CREB1 biology but downstream of core function.

  - term:
      id: GO:0007623
      label: circadian rhythm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 phosphorylation in the suprachiasmatic nucleus (SCN) participates in
        circadian rhythm generation. However, circadian rhythm is not a core function
        of CREB1 - it is a context-dependent downstream effect of its transcriptional
        activity in specific cell types.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        While CREB1 may regulate clock genes in the SCN, circadian rhythm is not a
        core function. The deep research review focuses on cAMP-responsive transcription,
        neuronal plasticity, metabolism, cancer, and immune function without emphasis
        on circadian rhythms. This appears to be over-annotation based on tissue-specific
        phenotypic effects.

  - term:
      id: GO:0008542
      label: visual learning
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may participate in visual learning through activity-dependent gene
        expression, similar to its role in memory formation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Phenotypic outcome of CREB1 transcriptional activity in specific neuronal
        contexts. Not a core molecular or cellular function.

  - term:
      id: GO:0009410
      label: response to xenobiotic stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may be activated by various xenobiotic stimuli that signal through
        cAMP/PKA pathways.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent response, not a core function. CREB1 responds to many stimuli
        that activate upstream kinases.

  - term:
      id: GO:0010629
      label: negative regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 can negatively regulate gene expression in certain contexts, though
        it
        primarily functions as a transcriptional activator.
      action: KEEP_AS_NON_CORE
      reason: >-
        CREB1 primarily activates transcription but can have repressive effects in
        specific contexts. Not the primary mode of action.

  - term:
      id: GO:0014823
      label: response to activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 is activated by neuronal activity through Ca2+/CaMK and other pathways,
        mediating activity-dependent gene expression.
      action: KEEP_AS_NON_CORE
      reason: >-
        Important for understanding CREB1's role in neurons but context-dependent.
        Core function is cAMP-responsive transcription.

  - term:
      id: GO:0030424
      label: axon
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may be detected in axons but its primary site of function is the nucleus
        where it regulates transcription.
      action: UNDECIDED
      reason: >-
        CREB1 is primarily a nuclear protein. Axonal localization would be unusual
        and
        requires verification. May reflect transport or non-canonical function.

  - term:
      id: GO:0030544
      label: Hsp70 protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may interact with Hsp70 chaperones for protein folding or stability.
      action: UNDECIDED
      reason: >-
        Limited evidence for functional significance of Hsp70 binding. May represent
        general chaperone interaction rather than specific functional binding.

  - term:
      id: GO:0032916
      label: positive regulation of transforming growth factor beta3 production
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may regulate TGF-beta3 expression through CRE elements in the TGF-beta3
        promoter.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specific downstream target regulation, not a core function. CREB1 regulates
        many target genes.

  - term:
      id: GO:0033762
      label: response to glucagon
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Glucagon signals through cAMP/PKA to activate CREB1 in hepatocytes, inducing
        gluconeogenic genes like PEPCK. This is a well-characterized metabolic role
        of CREB1.
      action: ACCEPT
      reason: >-
        Well-documented response - glucagon activates CREB1 through cAMP/PKA in liver
        to regulate gluconeogenesis. Directly relevant to core cAMP-responsive function.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "The phosphoenolpyruvate carboxykinase (PEPCK) promoter
            was used as a model system to explore the role of SRCAP in the regulation
            of transcription mediated by factors that utilize CBP as a coactivator"

  - term:
      id: GO:0034670
      label: chemotaxis to arachidonate
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may be involved in arachidonate-mediated chemotaxis signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent response, not a core CREB1 function.

  - term:
      id: GO:0035035
      label: histone acetyltransferase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 binds histone acetyltransferases CBP/p300 when phosphorylated at Ser-119.
        This is a core mechanism for transcriptional activation.
      action: ACCEPT
      reason: >-
        Core molecular function. CBP and p300 are histone acetyltransferases that
        CREB1
        recruits to activate transcription. The KID-KIX interaction is essential for
        CREB-mediated gene activation.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "SRCAP binds to CBP amino acids 280-460, a region that
            is important for CBP to function as a coactivator for CREB"

  - term:
      id: GO:0035094
      label: response to nicotine
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may be activated by nicotine through neuronal signaling pathways.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent response to a specific stimulus, not a core function.

  - term:
      id: GO:0035497
      label: cAMP response element binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Duplicate of IBA annotation. CRE binding is the defining DNA binding specificity
        of CREB1.
      action: ACCEPT
      reason: >-
        Core molecular function. IEA annotation consistent with IBA annotation.

  - term:
      id: GO:0036017
      label: response to erythropoietin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may be involved in erythropoietin signaling responses.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent signaling response, not a core function.

  - term:
      id: GO:0036120
      label: cellular response to platelet-derived growth factor stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may be activated by PDGF signaling through MAPK/RSK pathways.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent growth factor response. CREB1 responds to many upstream
        signals.

  - term:
      id: GO:0042220
      label: response to cocaine
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 is activated by cocaine in reward circuits through dopamine signaling
        and cAMP/PKA pathways.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent drug response in neurons, not a core function.

  - term:
      id: GO:0042981
      label: regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 regulates genes involved in apoptosis including BCL-2 family members
        (PMID:8798441). It generally promotes cell survival.
      action: KEEP_AS_NON_CORE
      reason: >-
        CREB1 regulates apoptosis-related genes but this is a downstream phenotypic
        effect of its transcriptional activity, not a core function.
      supported_by:
        - reference_id: PMID:8798441
          supporting_text: "CREB proteins function as positive regulators of the translocated
            bcl-2 allele in t(14;18) lymphomas"

  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 can positively regulate apoptosis in certain contexts, though it more
        commonly promotes survival.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent effect on apoptosis. CREB1 primarily promotes survival but
        can have pro-apoptotic effects in some settings.

  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 generally promotes cell survival through activation of anti-apoptotic
        genes like BCL-2.
      action: KEEP_AS_NON_CORE
      reason: >-
        CREB1 has pro-survival effects through transcriptional regulation of BCL-2
        and other genes, but this is a downstream phenotypic effect.
      supported_by:
        - reference_id: PMID:8798441
          supporting_text: "CREB proteins function as positive regulators of the translocated
            bcl-2 allele"

  - term:
      id: GO:0043278
      label: response to morphine
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 is activated by morphine through opioid receptor signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent drug response, not a core function.

  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CREB1 binds DNA in a sequence-specific manner to CRE elements. Parent term
        of
        more specific annotations.
      action: ACCEPT
      reason: >-
        Core molecular function. CREB1 recognizes the CRE sequence specifically.

  - term:
      id: GO:0045471
      label: response to ethanol
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may respond to ethanol through various neuronal signaling pathways.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent drug response, not a core function.

  - term:
      id: GO:0045600
      label: positive regulation of fat cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 promotes adipocyte differentiation through regulation of adipogenic
        genes in response to cAMP signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell type-specific differentiation role, downstream of core transcriptional
        function.

  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 activates gluconeogenic genes like PEPCK in response to glucagon/cAMP
        signaling in hepatocytes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Important metabolic role in liver but tissue-specific downstream effect of
        core cAMP-responsive transcription function.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "The phosphoenolpyruvate carboxykinase (PEPCK) promoter
            was used as a model system"

  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 positively regulates transcription when activated by phosphorylation.
      action: ACCEPT
      reason: >-
        Core biological process. CREB1 is primarily a transcriptional activator.

  - term:
      id: GO:0045899
      label: positive regulation of RNA polymerase II transcription 
        preinitiation complex assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may facilitate preinitiation complex assembly through recruitment of
        coactivators that interact with basal transcription machinery.
      action: ACCEPT
      reason: >-
        Mechanistically relevant to CREB1's role in transcriptional activation.

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 activates Pol II-dependent transcription when phosphorylated.
      action: ACCEPT
      reason: >-
        Core biological process directly related to CREB1's molecular function as
        a
        transcriptional activator.

  - term:
      id: GO:0046889
      label: positive regulation of lipid biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may regulate lipogenic gene expression in metabolic contexts.
      action: KEEP_AS_NON_CORE
      reason: >-
        Metabolic downstream effect, not a core function.

  - term:
      id: GO:0048145
      label: regulation of fibroblast proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may regulate fibroblast proliferation through growth factor signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell type-specific phenotypic effect, not a core function.

  - term:
      id: GO:0050821
      label: protein stabilization
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may regulate expression of genes involved in protein stability. CREB1
        itself is stabilized by sumoylation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Indirect effect through transcriptional regulation or relates to CREB1's own
        regulation, not a core function.

  - term:
      id: GO:0060251
      label: regulation of glial cell proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may regulate glial cell proliferation through neuronal signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell type-specific phenotypic effect, not a core function.

  - term:
      id: GO:0071300
      label: cellular response to retinoic acid
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may participate in retinoic acid responses through cross-talk with
        other signaling pathways.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent signaling response, not a core function.

  - term:
      id: GO:0071363
      label: cellular response to growth factor stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 is activated by various growth factors through MAPK/RSK and other
        signaling pathways.
      action: KEEP_AS_NON_CORE
      reason: >-
        General response category. Core function is cAMP-responsive transcription,
        but CREB1 also responds to growth factor signals.

  - term:
      id: GO:0071398
      label: cellular response to fatty acid
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may respond to fatty acid signaling in metabolic contexts.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent metabolic response, not a core function.

  - term:
      id: GO:0071560
      label: cellular response to transforming growth factor beta stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may participate in TGF-beta responses.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent signaling response, not a core function.

  - term:
      id: GO:1900273
      label: positive regulation of long-term synaptic potentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 plays important roles in long-term potentiation (LTP) through
        activity-dependent gene expression required for synaptic plasticity.
      action: KEEP_AS_NON_CORE
      reason: >-
        Well-documented neuronal function but this is a phenotypic outcome of CREB1's
        transcriptional activity in neurons, not a core molecular function.

  - term:
      id: GO:1902065
      label: response to L-glutamate
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 is activated by glutamate signaling through Ca2+/CaMK pathways in neurons.
      action: KEEP_AS_NON_CORE
      reason: >-
        Neuron-specific signaling response, not a core function.

  - term:
      id: GO:1903494
      label: response to dehydroepiandrosterone
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may respond to DHEA signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent hormonal response, not a core function.

  - term:
      id: GO:1904181
      label: positive regulation of membrane depolarization
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may regulate genes involved in neuronal excitability.
      action: KEEP_AS_NON_CORE
      reason: >-
        Downstream phenotypic effect in neurons, not a core function.

  - term:
      id: GO:1990090
      label: cellular response to nerve growth factor stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 is activated by NGF through MAPK/RSK pathways in neurons.
      action: KEEP_AS_NON_CORE
      reason: >-
        Neuron-specific growth factor response, not a core function.

  - term:
      id: GO:1990314
      label: cellular response to insulin-like growth factor stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may be activated by IGF signaling through PI3K/AKT pathway.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent growth factor response, not a core function.

  - term:
      id: GO:1990589
      label: ATF4-CREB1 transcription factor complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Duplicate of IBA annotation. CREB1 forms complexes with ATF4.
      action: ACCEPT
      reason: >-
        Valid cellular component. IEA annotation consistent with IBA annotation.

  - term:
      id: GO:1990763
      label: arrestin family protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 interacts with beta-arrestin1 (ARRB1) which has a nuclear function in
        GPCR signaling and histone acetylation (PMID:16325578).
      action: ACCEPT
      reason: >-
        Specific protein binding annotation more informative than generic protein
        binding. ARRB1 interaction is functionally relevant for CREB-dependent
        transcription.

  - term:
      id: GO:1990910
      label: response to hypobaric hypoxia
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may respond to hypoxic stress.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent stress response, not a core function.

  - term:
      id: GO:2000224
      label: regulation of testosterone biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CREB1 may regulate steroidogenic gene expression in gonadal cells.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue-specific downstream effect, not a core function.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        CREB1 localizes to the nucleoplasm where it functions as a transcription factor.
      action: ACCEPT
      reason: >-
        Core cellular component. IDA annotation from immunofluorescence data.

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: NAS
    original_reference_id: PMID:12871976
    review:
      summary: >-
        CREB1 is a nuclear transcription factor. PMID:12871976 identifies CREB1 as
        a
        nuclear co-factor that forms complexes with ATF4.
      action: ACCEPT
      reason: >-
        Core cellular component supported by literature.
      supported_by:
        - reference_id: PMID:12871976
          supporting_text: "we have identified the closely related ATF1 and CREB1
            as nuclear co-factors that form in vivo complexes with endogenous ATF4"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: NAS
    original_reference_id: PMID:1655749
    review:
      summary: >-
        CREB1 is a nuclear transcription factor.
      action: ACCEPT
      reason: >-
        Core cellular component.

      supported_by:
        - reference_id: PMID:1655749
          supporting_text: The cAMP-regulated enhancer-binding protein ATF-1 
            activates transcription in response to cAMP-dependent protein kinase
            A.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:1655749
    review:
      summary: >-
        PMID:1655749 demonstrates that CREB family members (ATF-1 and CREB) activate
        transcription in response to PKA.
      action: ACCEPT
      reason: >-
        Core biological process. Direct experimental evidence for transcriptional
        activation.
      supported_by:
        - reference_id: PMID:1655749
          supporting_text: "ATF-1 is as active as CREB in its ability to mediate the
            transcriptional effects of PKA"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: NAS
    original_reference_id: PMID:20102225
    review:
      summary: >-
        CREB1 is a nuclear protein.
      action: ACCEPT
      reason: >-
        Core cellular component.

      supported_by:
        - reference_id: PMID:20102225
          supporting_text: Identification of bZIP interaction partners of viral 
            proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: NAS
    original_reference_id: PMID:20102225
    review:
      summary: >-
        CREB1 regulates Pol II transcription.
      action: ACCEPT
      reason: >-
        Core biological process.

      supported_by:
        - reference_id: PMID:20102225
          supporting_text: Identification of bZIP interaction partners of viral 
            proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:11522779
    review:
      summary: >-
        PMID:11522779 demonstrates that CREB mediates PKA-activated transcription
        through CRE elements in the PEPCK promoter.
      action: ACCEPT
      reason: >-
        Core molecular function with direct experimental evidence.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "SRCAP functions as a coactivator for PKA-activated factors
            such as CREB"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:11522779
    review:
      summary: >-
        CREB1 functions in the nucleus.
      action: ACCEPT
      reason: >-
        Core cellular component.

      supported_by:
        - reference_id: PMID:11522779
          supporting_text: 2001 Aug 24. Regulation of cAMP-responsive 
            element-binding protein-mediated transcription by the 
            SNF2/SWI-related protein, SRCAP.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:11522779
    review:
      summary: >-
        PMID:11522779 shows CREB activates Pol II transcription at the PEPCK promoter.
      action: ACCEPT
      reason: >-
        Core biological process with direct experimental evidence.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "transcription of a PEPCK chloramphenicol acetyltransferase
            (CAT) reporter gene activated by protein kinase A (PKA) is enhanced 7-fold
            by SRCAP"

  - term:
      id: GO:0141156
      label: cAMP/PKA signal transduction
    evidence_type: IDA
    original_reference_id: PMID:11522779
    review:
      summary: >-
        PMID:11522779 demonstrates CREB's role as a downstream effector of PKA signaling.
      action: ACCEPT
      reason: >-
        Core biological process with direct experimental evidence.
      supported_by:
        - reference_id: PMID:11522779
          supporting_text: "SRCAP functions as a coactivator for PKA-activated factors
            such as CREB"

  - term:
      id: GO:0141156
      label: cAMP/PKA signal transduction
    evidence_type: IDA
    original_reference_id: PMID:25644539
    review:
      summary: >-
        PMID:25644539 demonstrates CREB1 involvement in cAMP/PKA signaling in the
        context of aortic valve calcification.
      action: ACCEPT
      reason: >-
        Core biological process with experimental evidence.

      supported_by:
        - reference_id: PMID:25644539
          supporting_text: Feb 2. Adenosine derived from ecto-nucleotidases in 
            calcific aortic valve disease promotes mineralization through A2a 
            adenosine receptor.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-199298
    review:
      summary: >-
        Reactome pathway for AKT phosphorylation of CREB1 places CREB1 in nucleoplasm.
      action: ACCEPT
      reason: >-
        Core cellular component supported by pathway database.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-199895
    review:
      summary: >-
        Reactome pathway for RSK1/2/3 phosphorylation of CREB.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-199917
    review:
      summary: >-
        Reactome pathway for MAPKAPK2 phosphorylation of CREB.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-199935
    review:
      summary: >-
        Reactome pathway for MSK1 activation of CREB.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2399996
    review:
      summary: >-
        Reactome pathway for AKT1 E17K mutant phosphorylation of CREB1.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-442724
    review:
      summary: >-
        Reactome pathway for RSK phosphorylation of CREB1.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9612501
    review:
      summary: >-
        Reactome pathway for SGK phosphorylation of CREB1.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9612514
    review:
      summary: >-
        Reactome pathway for p-S133 CREB binding to EGR1 promoter.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9613451
    review:
      summary: >-
        Reactome pathway for CREB1 binding to ID1 and ID3 genes.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9623341
    review:
      summary: >-
        Reactome pathway for CREB1 binding to CCND1 promoter.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9662708
    review:
      summary: >-
        Reactome pathway for CREB binding to IL6 promoter.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664332
    review:
      summary: >-
        Reactome pathway for CREB1 binding to IL-10 promoter.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9824653
    review:
      summary: >-
        Reactome pathway for CREB1 binding to MITF promoter.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9825848
    review:
      summary: >-
        Reactome pathway for CREB1 at DCT promoter.
      action: ACCEPT
      reason: >-
        Core cellular component.

  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CREB1 promotes cell survival through activation of anti-apoptotic genes like
        BCL-2.
      action: KEEP_AS_NON_CORE
      reason: >-
        Downstream phenotypic effect of transcriptional activity.

  - term:
      id: GO:0042789
      label: mRNA transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:25644539
    review:
      summary: >-
        CREB1 mediates mRNA transcription by Pol II.
      action: ACCEPT
      reason: >-
        Core biological process related to transcriptional function.

      supported_by:
        - reference_id: PMID:25644539
          supporting_text: Feb 2. Adenosine derived from ecto-nucleotidases in 
            calcific aortic valve disease promotes mineralization through A2a 
            adenosine receptor.
  - term:
      id: GO:1904322
      label: cellular response to forskolin
    evidence_type: IDA
    original_reference_id: PMID:25644539
    review:
      summary: >-
        Forskolin activates adenylyl cyclase and cAMP/PKA signaling, which activates
        CREB1. CREB1 is a key mediator of forskolin responses.
      action: ACCEPT
      reason: >-
        Directly relevant to CREB1's core function in cAMP signaling. Forskolin is
        a standard tool for activating CREB through the cAMP/PKA pathway.

      supported_by:
        - reference_id: PMID:25644539
          supporting_text: Feb 2. Adenosine derived from ecto-nucleotidases in 
            calcific aortic valve disease promotes mineralization through A2a 
            adenosine receptor.
  - term:
      id: GO:0014074
      label: response to purine-containing compound
    evidence_type: IDA
    original_reference_id: PMID:25644539
    review:
      summary: >-
        CREB1 responds to adenosine and other purine compounds through cAMP signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Related to cAMP signaling but general response category.

      supported_by:
        - reference_id: PMID:25644539
          supporting_text: Feb 2. Adenosine derived from ecto-nucleotidases in 
            calcific aortic valve disease promotes mineralization through A2a 
            adenosine receptor.
  - term:
      id: GO:1990837
      label: sequence-specific double-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:28473536
    review:
      summary: >-
        PMID:28473536 analyzed DNA binding specificities of transcription factors
        including CREB1.
      action: ACCEPT
      reason: >-
        Core molecular function describing DNA binding specificity.

      supported_by:
        - reference_id: PMID:28473536
          supporting_text: Impact of cytosine methylation on DNA binding 
            specificities of human transcription factors.
  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CREB1 is a transcriptional activator.
      action: ACCEPT
      reason: >-
        Core molecular function.

  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: ISA
    original_reference_id: GO_REF:0000113
    review:
      summary: >-
        CREB1 associates with chromatin at CRE-containing promoters.
      action: ACCEPT
      reason: >-
        Valid cellular component.

  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    evidence_type: ISA
    original_reference_id: GO_REF:0000113
    review:
      summary: >-
        CREB1 is a Pol II-specific transcription factor based on TFClass database.
      action: ACCEPT
      reason: >-
        Core molecular function.

  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:19861239
    review:
      summary: >-
        PMID:19861239 shows CREB1 activates gamma-globin gene expression through the
        G-CRE element.
      action: ACCEPT
      reason: >-
        Core molecular function with direct experimental evidence.
      supported_by:
        - reference_id: PMID:19861239
          supporting_text: "enforced expression studies with pLen-cJun and a Ggamma-promoter
            (-1500 to +36) luciferase reporter were completed; we observed a concentration-dependent
            increase in luciferase activity with pLen-cJun similar to that produced
            by CREB1 enforced expression"

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CREB1 activates Pol II transcription.
      action: ACCEPT
      reason: >-
        Core biological process.

  - term:
      id: GO:0071300
      label: cellular response to retinoic acid
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CREB1 may participate in retinoic acid responses.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent signaling response.

  - term:
      id: GO:1990589
      label: ATF4-CREB1 transcription factor complex
    evidence_type: IDA
    original_reference_id: PMID:12871976
    review:
      summary: >-
        PMID:12871976 identifies CREB1 as forming complexes with ATF4 that activate
        the Grp78 promoter through ATF/CRE sites.
      action: ACCEPT
      reason: >-
        Valid cellular component with direct experimental evidence.
      supported_by:
        - reference_id: PMID:12871976
          supporting_text: "we have identified the closely related ATF1 and CREB1
            as nuclear co-factors that form in vivo complexes with endogenous ATF4"

  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:23382074
    review:
      summary: >-
        PMID:23382074 identifies CREB1 interaction with SIRT1 deacetylase. More
        informative than generic protein binding.
      action: ACCEPT
      reason: >-
        Specific binding annotation. CREB1 interacts with various enzymes that
        regulate its activity.

      supported_by:
        - reference_id: PMID:23382074
          supporting_text: Feb 4. A high-confidence interaction map identifies 
            SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator
            complex.
  - term:
      id: GO:0007623
      label: circadian rhythm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Circadian rhythm annotation based on sequence similarity to mouse CREB1.
        While CREB1 participates in SCN signaling, circadian rhythm is not a core
        function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Over-annotation. CREB1's core function is cAMP-responsive transcription.
        Circadian rhythm involvement is tissue-specific and downstream of core function.

  - term:
      id: GO:0033762
      label: response to glucagon
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Glucagon response is well-documented for CREB1 in hepatocytes.
      action: ACCEPT
      reason: >-
        Well-characterized response directly related to cAMP/PKA signaling function.

  - term:
      id: GO:0045600
      label: positive regulation of fat cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CREB1 promotes adipocyte differentiation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell type-specific downstream effect.

  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CREB1 activates transcription.
      action: ACCEPT
      reason: >-
        Core biological process.

  - term:
      id: GO:0046889
      label: positive regulation of lipid biosynthetic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CREB1 may regulate lipogenic genes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Metabolic downstream effect.

  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IDA
    original_reference_id: PMID:9065434
    review:
      summary: >-
        PMID:9065434 demonstrates CREB binding to the IL-2 promoter CRE.
      action: ACCEPT
      reason: >-
        Core molecular function with experimental evidence.

      supported_by:
        - reference_id: PMID:9065434
          supporting_text: Constitutive binding of the transcription factor 
            interleukin-2 (IL-2) enhancer binding factor to the IL-2 promoter.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18160048
    review:
      summary: >-
        Generic protein binding from interaction with LYL1.
      action: REMOVE
      reason: >-
        Uninformative generic term.

      supported_by:
        - reference_id: PMID:18160048
          supporting_text: Lyl1 interacts with CREB1 and alters expression of 
            CREB1 target genes.
  - term:
      id: GO:0050821
      label: protein stabilization
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CREB1 may contribute to protein stabilization.
      action: KEEP_AS_NON_CORE
      reason: >-
        Indirect effect, not a core function.

  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:19861239
    review:
      summary: >-
        PMID:19861239 demonstrates CREB1 transcription factor activity at gamma-globin
        promoter.
      action: ACCEPT
      reason: >-
        Core molecular function with experimental evidence.
      supported_by:
        - reference_id: PMID:19861239
          supporting_text: "Using chromatin immunoprecipitation assays we showed comparable
            in vivo cJun and CREB1 binding to the G-CRE region"

  - term:
      id: GO:0010944
      label: negative regulation of transcription by competitive promoter 
        binding
    evidence_type: IDA
    original_reference_id: PMID:19861239
    review:
      summary: >-
        PMID:19861239 shows competitive binding at the gamma-globin CRE where CREB1
        and cJun can compete for binding.
      action: ACCEPT
      reason: >-
        Valid regulatory mechanism - competition between transcription factors at
        shared binding sites.
      supported_by:
        - reference_id: PMID:19861239
          supporting_text: "Protein-protein interactions were confirmed between cJun/ATF-2
            and CREB1/ATF-2 but not between CREB1 and cJun"

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:19861239
    review:
      summary: >-
        PMID:19861239 shows CREB1 activates gamma-globin transcription.
      action: ACCEPT
      reason: >-
        Core biological process with experimental evidence.
      supported_by:
        - reference_id: PMID:19861239
          supporting_text: "we observed a concentration-dependent increase in luciferase
            activity with pLen-cJun similar to that produced by CREB1 enforced expression"

  - term:
      id: GO:0000791
      label: euchromatin
    evidence_type: IDA
    original_reference_id: PMID:19861239
    review:
      summary: >-
        PMID:19861239 shows CREB1 binding to the actively transcribed gamma-globin
        locus in euchromatin.
      action: ACCEPT
      reason: >-
        Valid cellular component - CREB1 binds actively transcribed chromatin regions.

      supported_by:
        - reference_id: PMID:19861239
          supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene 
            expression via an upstream cAMP response element.
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IDA
    original_reference_id: PMID:19861239
    review:
      summary: >-
        PMID:19861239 demonstrates CREB1 binding to the gamma-globin G-CRE.
      action: ACCEPT
      reason: >-
        Core molecular function with experimental evidence.
      supported_by:
        - reference_id: PMID:19861239
          supporting_text: "we observed cJun and CREB1 binding to the G-CRE in vitro
            by electrophoretic mobility shift assay"

  - term:
      id: GO:0035497
      label: cAMP response element binding
    evidence_type: IDA
    original_reference_id: PMID:19861239
    review:
      summary: >-
        PMID:19861239 demonstrates CREB1 binding to the G-CRE element.
      action: ACCEPT
      reason: >-
        Core molecular function with direct experimental evidence.
      supported_by:
        - reference_id: PMID:19861239
          supporting_text: "Using chromatin immunoprecipitation assays we showed comparable
            in vivo cJun and CREB1 binding to the G-CRE region"

  - term:
      id: GO:0061629
      label: RNA polymerase II-specific DNA-binding transcription factor binding
    evidence_type: IPI
    original_reference_id: PMID:19861239
    review:
      summary: >-
        PMID:19861239 shows CREB1 interacts with c-Jun at the gamma-globin promoter.
      action: ACCEPT
      reason: >-
        Valid molecular function - CREB1 interacts with other transcription factors.
      supported_by:
        - reference_id: PMID:19861239
          supporting_text: "Promoter pull-down assay followed by sequential western
            blot analysis confirmed co-localization of cJun, CREB1, and ATF-2 on the
            G-CRE"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21172805
    review:
      summary: >-
        Generic protein binding from interaction with TOX3.
      action: REMOVE
      reason: >-
        Uninformative generic term.

      supported_by:
        - reference_id: PMID:21172805
          supporting_text: Dec 15. TOX3 is a neuronal survival factor that 
            induces transcription depending on the presence of CITED1 or 
            phosphorylated CREB in the transcriptionally active complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18316612
    review:
      summary: >-
        Generic protein binding from interaction with AEG-1.
      action: REMOVE
      reason: >-
        Uninformative generic term.

      supported_by:
        - reference_id: PMID:18316612
          supporting_text: Molecular basis of nuclear factor-kappaB activation 
            by astrocyte elevated gene-1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16325578
    review:
      summary: >-
        Generic protein binding from interaction with beta-arrestin1 (ARRB1).
      action: REMOVE
      reason: >-
        Uninformative generic term. The ARRB1 interaction is better captured by
        GO:1990763 (arrestin family protein binding).

      supported_by:
        - reference_id: PMID:16325578
          supporting_text: 'A nuclear function of beta-arrestin1 in GPCR signaling:
            regulation of histone acetylation and gene transcription.'
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IDA
    original_reference_id: PMID:8798441
    review:
      summary: >-
        PMID:8798441 demonstrates CREB binding to the bcl-2 CRE and transcriptional
        activation of the bcl-2 promoter.
      action: ACCEPT
      reason: >-
        Core molecular function with experimental evidence.
      supported_by:
        - reference_id: PMID:8798441
          supporting_text: "Electrophoretic mobility shift assays with the bcl-2 CRE
            demonstrated complexes with mobilities identical to those with a consensus
            CRE"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:8798441
    review:
      summary: >-
        CREB1 is a nuclear transcription factor.
      action: ACCEPT
      reason: >-
        Core cellular component.

      supported_by:
        - reference_id: PMID:8798441
          supporting_text: CREB proteins function as positive regulators of the 
            translocated bcl-2 allele in t(14;18) lymphomas.
  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:8798441
    review:
      summary: >-
        MISANNOTATION: CREB1 is a bZIP transcription factor that is extensively
        PHOSPHORYLATED by kinases (CaMK1/2/4, AKT, RPS6KA3/4/5, SGK1, TSSK4, HIPK2)
        at Ser-119, Ser-128, and Ser-257. PMID:8798441 describes "phosphorylated CREB
        was present in DHL-4 cells" - CREB1 is the SUBSTRATE of phosphorylation, not
        the enzyme. CREB1 has no kinase activity (EC number). This is a transcription
        factor that regulates bcl-2 expression when phosphorylated. The paper shows
        CREB1 being phosphorylated by upstream kinases like PKA and PKC, not CREB1
        catalyzing phosphorylation.
      action: REMOVE
      reason: >-
        Incorrect annotation. CREB1 is phosphorylated by upstream kinases - it is
        a
        substrate, not an enzyme. CREB1 has no kinase domain or kinase activity.
      supported_by:
        - reference_id: PMID:8798441
          supporting_text: "Electrophoretic mobility shift assay with an antibody
            specific to the phosphorylated cAMP response-binding protein (CREB) demonstrated
            that phosphorylated CREB was present in DHL-4 cells"

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:8798441
    review:
      summary: >-
        PMID:8798441 shows CREB proteins activate bcl-2 transcription through CRE
        elements.
      action: ACCEPT
      reason: >-
        Core biological process with experimental evidence.
      supported_by:
        - reference_id: PMID:8798441
          supporting_text: "CREB proteins function as positive regulators of the translocated
            bcl-2 allele in t(14;18) lymphomas"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14506290
    review:
      summary: >-
        Generic protein binding from interaction with CRTC3 coactivator.
      action: REMOVE
      reason: >-
        Uninformative generic term. CRTC interaction is better represented by
        GO:0001223 (transcription coactivator binding).

      supported_by:
        - reference_id: PMID:14506290
          supporting_text: Identification of a family of cAMP response 
            element-binding protein coactivators by genome-scale functional 
            analysis in mammalian cells.
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: TAS
    original_reference_id: PMID:2974179
    review:
      summary: >-
        PMID:2974179 describes the cloning of CREB and establishes its role in cAMP
        signal transduction.
      action: ACCEPT
      reason: >-
        Core biological process. CREB1 is a key effector of cAMP signaling pathways.

      supported_by:
        - reference_id: PMID:2974179
          supporting_text: 'Cyclic AMP-responsive DNA-binding protein: structure based
            on a cloned placental cDNA.'
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000113
    title: Gene Ontology annotation of human sequence-specific DNA binding 
      transcription factors (DbTFs) based on the TFClass database
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:1655749
    title: The cAMP-regulated enhancer-binding protein ATF-1 activates 
      transcription in response to cAMP-dependent protein kinase A.
    findings:
      - statement: ATF-1 and CREB can homodimerize and heterodimerize
      - statement: Both bind CRE elements and mediate PKA-dependent 
          transcription
      - statement: ATF-1 is as active as CREB in mediating PKA transcriptional 
          effects
  - id: PMID:11522779
    title: Regulation of cAMP-responsive element-binding protein-mediated 
      transcription by the SNF2/SWI-related protein, SRCAP.
    findings:
      - statement: SRCAP functions as a coactivator for PKA-activated CREB
      - statement: CREB activates PEPCK promoter through CRE elements
      - statement: SRCAP enhances PKA-activated transcription 7-fold
  - id: PMID:12871976
    title: "Induction of Grp78/BiP by translational block: activation of the Grp78
      promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic
      reticulum stress elements."
    findings:
      - statement: CREB1 forms complexes with ATF4 in the nucleus
      - statement: ATF4-CREB1 complexes activate Grp78 promoter through ATF/CRE 
          sites
      - statement: ER stress induces CREB1 phosphorylation
  - id: PMID:8798441
    title: CREB proteins function as positive regulators of the translocated 
      bcl-2 allele in t(14;18) lymphomas.
    findings:
      - statement: Phosphorylated CREB binds bcl-2 CRE element
      - statement: CREB activates bcl-2 promoter activity
      - statement: PMA treatment increases phosphorylated CREB
  - id: PMID:19861239
    title: cJun modulates Ggamma-globin gene expression via an upstream cAMP 
      response element.
    findings:
      - statement: CREB1 binds G-CRE element in vivo and in vitro
      - statement: CREB1 activates gamma-globin transcription
      - statement: CREB1 co-localizes with cJun and ATF-2 on the G-CRE
  - id: PMID:2974179
    title: Cyclic AMP-responsive DNA-binding protein - structure based on a 
      cloned placental cDNA.
    findings:
      - statement: Original cloning of CREB
      - statement: Establishes CREB role in cAMP signal transduction
  - id: PMID:10722738
    title: cAMP-independent activation of the adenovirus type 12 E2 promoter 
      correlates with the recruitment of CREB-1/ATF-1, E1A(12S), and CBP to the 
      E2-CRE.
    findings: []
  - id: PMID:15733869
    title: Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic 
      AMP response element binding protein, CREB.
    findings: []
  - id: PMID:15964553
    title: TSSK5, a novel member of the testis-specific serine/threonine kinase 
      family, phosphorylates CREB at Ser-133, and stimulates the CRE/CREB 
      responsive pathway.
    findings: []
  - id: PMID:16799563
    title: An ARC/Mediator subunit required for SREBP control of cholesterol and
      lipid homeostasis.
    findings: []
  - id: PMID:20102225
    title: Identification of bZIP interaction partners of viral proteins HBZ, 
      MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
    findings: []
  - id: PMID:20159610
    title: PML/RARalpha targets promoter regions containing PU.1 consensus and 
      RARE half sites in acute promyelocytic leukemia.
    findings: []
  - id: PMID:20541704
    title: GSK-3 promotes conditional association of CREB and its coactivators 
      with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.
    findings: []
  - id: PMID:20936779
    title: A human MAP kinase interactome.
    findings: []
  - id: PMID:21418524
    title: Substrate preference and phosphatidylinositol monophosphate 
      inhibition of the catalytic domain of the Per-Arnt-Sim domain kinase 
      PASKIN.
    findings: []
  - id: PMID:21988832
    title: Toward an understanding of the protein interaction network of the 
      human liver.
    findings: []
  - id: PMID:25609649
    title: Proteomic analyses reveal distinct chromatin-associated and soluble 
      transcription factor complexes.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:23661758
    title: Networks of bZIP protein-protein interactions diversified over a 
      billion years of evolution.
    findings: []
  - id: PMID:25644539
    title: Adenosine derived from ecto-nucleotidases in calcific aortic valve 
      disease promotes mineralization through A2a adenosine receptor.
    findings: []
  - id: PMID:28473536
    title: Impact of cytosine methylation on DNA binding specificities of human 
      transcription factors.
    findings: []
  - id: PMID:23382074
    title: A high-confidence interaction map identifies SIRT1 as a mediator of 
      acetylation of USP22 and the SAGA coactivator complex.
    findings: []
  - id: PMID:9065434
    title: Constitutive binding of the transcription factor interleukin-2 (IL-2)
      enhancer binding factor to the IL-2 promoter.
    findings: []
  - id: PMID:18160048
    title: Lyl1 interacts with CREB1 and alters expression of CREB1 target 
      genes.
    findings: []
  - id: PMID:21172805
    title: TOX3 is a neuronal survival factor that induces transcription 
      depending on the presence of CITED1 or phosphorylated CREB in the 
      transcriptionally active complex.
    findings: []
  - id: PMID:18316612
    title: Molecular basis of nuclear factor-kappaB activation by astrocyte 
      elevated gene-1.
    findings: []
  - id: PMID:16325578
    title: "A nuclear function of beta-arrestin1 in GPCR signaling: regulation of
      histone acetylation and gene transcription."
    findings: []
  - id: PMID:14506290
    title: Identification of a family of cAMP response element-binding protein 
      coactivators by genome-scale functional analysis in mammalian cells.
    findings: []
  - id: Reactome:R-HSA-199298
    title: AKT phosphorylation of CREB1
    findings: []
  - id: Reactome:R-HSA-199895
    title: RSK1/2/3 phosphorylation of CREB
    findings: []
  - id: Reactome:R-HSA-199917
    title: MAPKAPK2 phosphorylation of CREB
    findings: []
  - id: Reactome:R-HSA-199935
    title: MSK1 activation of CREB
    findings: []
  - id: Reactome:R-HSA-2399996
    title: AKT1 E17K mutant phosphorylation of CREB1
    findings: []
  - id: Reactome:R-HSA-442724
    title: RSK phosphorylation of CREB1
    findings: []
  - id: Reactome:R-HSA-9612501
    title: SGK phosphorylation of CREB1
    findings: []
  - id: Reactome:R-HSA-9612514
    title: p-S133 CREB binding to EGR1 promoter
    findings: []
  - id: Reactome:R-HSA-9613451
    title: CREB1 binding to ID1 and ID3 genes
    findings: []
  - id: Reactome:R-HSA-9623341
    title: CREB1 binding to CCND1 promoter
    findings: []
  - id: Reactome:R-HSA-9662708
    title: CREB binding to IL6 promoter
    findings: []
  - id: Reactome:R-HSA-9664332
    title: CREB1 binding to IL-10 promoter
    findings: []
  - id: Reactome:R-HSA-9824653
    title: CREB1 binding to MITF promoter
    findings: []
  - id: Reactome:R-HSA-9825848
    title: CREB1 at DCT promoter
    findings: []
  - id: file:human/CREB1/CREB1-deep-research-falcon.md
    title: Deep research report on CREB1
    findings: []

core_functions:
  - molecular_function:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    description: >-
      bZIP transcription factor that binds cAMP response elements (CRE; TGACGTCA)
      as homo- or heterodimers to activate transcription of target genes. Core
      defining function of CREB1 supported by extensive structural and functional
      studies.
    directly_involved_in:
      - id: GO:0045944
        label: positive regulation of transcription by RNA polymerase II
      - id: GO:0141156
        label: cAMP/PKA signal transduction
    locations:
      - id: GO:0005654
        label: nucleoplasm
  - molecular_function:
      id: GO:0035497
      label: cAMP response element binding
    description: >-
      Binds the palindromic CRE sequence (TGACGTCA) via its bZIP domain. This is the
      defining DNA binding specificity that distinguishes CREB family members from
      other bZIP transcription factors.
    locations:
      - id: GO:0000785
        label: chromatin
  - molecular_function:
      id: GO:0001223
      label: transcription coactivator binding
    description: >-
      Phosphorylation at Ser-119 by PKA and other kinases enables recruitment of
      CBP/p300 coactivators via the KID-KIX interaction. This coactivator binding
      is essential for CREB-mediated transcriptional activation.
    directly_involved_in:
      - id: GO:0141156
        label: cAMP/PKA signal transduction

proposed_new_terms: []

suggested_questions: []

suggested_experiments: []

CREB1

Gene Description

Existing Annotations Review

Core Functions

bZIP transcription factor that binds cAMP response elements (CRE; TGACGTCA) as homo- or heterodimers to activate transcription of target genes. Core defining function of CREB1 supported by extensive structural and functional studies.

Binds the palindromic CRE sequence (TGACGTCA) via its bZIP domain. This is the defining DNA binding specificity that distinguishes CREB family members from other bZIP transcription factors.

Phosphorylation at Ser-119 by PKA and other kinases enables recruitment of CBP/p300 coactivators via the KID-KIX interaction. This coactivator binding is essential for CREB-mediated transcriptional activation.

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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