ATF4 (Activating Transcription Factor 4) is a bZIP transcription factor that serves as the central effector of the Integrated Stress Response (ISR). Under basal conditions, ATF4 translation is suppressed by upstream open reading frames (uORFs) in its 5'UTR. Upon cellular stress (ER stress, amino acid deprivation, oxidative stress, mitochondrial stress), phosphorylation of eIF2alpha by stress-sensing kinases (PERK, GCN2, HRI, PKR) leads to preferential translation of ATF4. In the nucleus, ATF4 heterodimerizes with other bZIP transcription factors (CHOP/DDIT3, C/EBP family members, CREB, ATF3) via its leucine zipper domain and binds to cAMP response elements (CRE) and C/EBP-ATF response elements (CARE/AARE) to activate transcription of stress-responsive genes involved in amino acid metabolism (ASNS, SLC7A11), redox homeostasis, autophagy, and apoptosis. ATF4 also plays non-stress roles in osteoblast differentiation and bone development.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: ATF4 is a bZIP transcription factor that binds to CRE and CARE/AARE sequences in promoters to regulate transcription. This molecular function annotation is appropriate and consistent with its well-established role as a sequence-specific DNA-binding transcription factor. Reason: ATF4's binding to specific regulatory sequences (CRE, CARE/AARE) is extensively documented and represents a core molecular function (PMID:12871976, PMID:11960987). Supporting Evidence: PMID:12871976 2003 Jul 18. 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. PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. file:human/ATF4/ATF4-deep-research-cyberian.md model: deep-research |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: ATF4 functions predominantly as a transcriptional activator for stress-responsive genes including ASNS, GRP78/BiP, CHOP, and TRB3. This annotation accurately reflects its primary molecular function. Reason: ATF4's transcriptional activator function is well-documented. Overexpression of ATF4 increases promoter-driven transcription of target genes (PMID:11960987, PMID:12871976). Supporting Evidence: PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. PMID:12871976 2003 Jul 18. 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. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: ATF4 localizes to the nucleus where it functions as a transcription factor. Nuclear localization has been demonstrated by multiple experimental approaches. Reason: Nuclear localization is essential for ATF4's function as a transcription factor and is well-documented (UniProt, PMID:23123191, PMID:16682973). Supporting Evidence: PMID:23123191 Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: ATF4 regulates transcription of numerous genes in response to cellular stress. This biological process annotation captures its core function. Reason: Regulation of pol II transcription is a central function of ATF4, documented extensively in the ISR and stress response literature. Supporting Evidence: PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. |
| GO:1990589 ATF4-CREB1 transcription factor complex | IBA GO_REF:0000033 | ACCEPT | Summary: ATF4 forms heterodimeric complexes with CREB1 to regulate target gene expression. This complex was identified in the context of GRP78/BiP regulation. Reason: ATF4-CREB1 complex formation is documented experimentally (PMID:12871976). The IBA annotation is consistent with this evidence. Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:1990590 ATF1-ATF4 transcription factor complex | IBA GO_REF:0000033 | ACCEPT | Summary: ATF4 forms heterodimeric complexes with ATF1. This was demonstrated in the context of stress-induced transcription. Reason: ATF4-ATF1 complex formation is documented (PMID:12871976). Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: ATF4 binds DNA as part of its transcription factor activity. This is a general term appropriate for IEA evidence. Reason: DNA binding is well-established for ATF4 as a bZIP transcription factor. The more specific term GO:0000977 is also annotated with better evidence. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: ATF4 is a well-established transcription factor. This IEA annotation is consistent with experimental evidence. Reason: Transcription factor activity is a core function of ATF4, confirmed by multiple experimental studies. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization is well-established for ATF4. Duplicate of IBA annotation. Reason: Consistent with IBA annotation and experimental evidence. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: ATF4 is synthesized in the cytoplasm and can shuttle between cytoplasm and nucleus. Under stress, ATF4 accumulates in the nucleus, but cytoplasmic localization is part of its normal biology. Reason: ATF4 is translated in the cytoplasm and can localize there under basal conditions before stress-induced nuclear accumulation (UniProt). |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ATF4 has been reported to localize to the centrosome based on interaction with NEK6 and colocalization studies. This appears to be a non-canonical localization. Reason: While documented (PMID:20873783), centrosomal localization is not central to ATF4's primary function as a stress-response transcription factor. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ATF4 plasma membrane localization may relate to interaction with GABA-B receptors in neurons (by similarity to rat). This is a specialized context. Reason: Membrane localization via GABBR interaction is a specialized neuronal function, not the core stress-response role. |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: ATF4 participates in DNA-templated transcription as a transcription factor. This is a broad annotation appropriate for IEA. Reason: Consistent with ATF4's role as a transcription factor. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: ATF4 regulates transcription of stress-responsive genes. This is a core function. Reason: Consistent with ATF4's established role as a transcriptional regulator. |
| GO:0016607 nuclear speck | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ATF4 can be recruited to nuclear speckles following interaction with EP300/p300. Reason: Nuclear speckle localization is context-dependent and related to EP300 interaction (PMID:16219772), not a primary localization. |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ATF4, particularly in partnership with CHOP, can regulate apoptosis during prolonged ER stress. However, this is an outcome of chronic stress signaling rather than ATF4's primary function. Reason: ATF4's pro-apoptotic role is context-dependent (chronic stress with CHOP) and represents a downstream consequence rather than core function. |
| GO:0048511 rhythmic process | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: ATF4 has been implicated in circadian regulation of gene expression through binding to CRE elements in clock gene promoters. Reason: While ATF4 can regulate circadian genes, this is a secondary function not central to its ISR role. |
| GO:0005515 protein binding | IPI PMID:11238952 ATF4 degradation relies on a phosphorylation-dependent inter... | MODIFY | Summary: ATF4 interacts with BTRC (beta-TrCP) as part of the SCF ubiquitin ligase complex that targets ATF4 for degradation. This is a functionally relevant interaction. Reason: Protein binding is too vague. The specific interaction is with BTRC as a substrate of the SCF ubiquitin ligase for proteasomal degradation. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:11238952 ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. |
| GO:0005515 protein binding | IPI PMID:12743605 SKIP3, a novel Drosophila tribbles ortholog, is overexpresse... | MODIFY | Summary: Interaction with TRIB3, a pseudokinase that inhibits ATF4 transactivation activity. Reason: The interaction with TRIB3 represents a specific regulatory mechanism. A more specific term would be preferred. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:12743605 SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia. |
| GO:0005515 protein binding | IPI PMID:12812986 DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associa... | MODIFY | Summary: Interaction with DISC1 (Disrupted in Schizophrenia 1). DISC1 inhibits ATF4 by disrupting its dimerization and DNA-binding. Reason: This represents a specific regulatory interaction affecting ATF4 transcription factor activity. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:12812986 DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. |
| GO:0005515 protein binding | IPI PMID:12860379 Functional interaction of the subunit 3 of RNA polymerase II... | MODIFY | Summary: Interaction with RPB3 (POLR2C), a subunit of RNA polymerase II. This reflects ATF4's function as a transcription factor. Reason: This is a functionally relevant interaction with the transcription machinery. Proposed replacements: general transcription initiation factor binding Supporting Evidence: PMID:12860379 Functional interaction of the subunit 3 of RNA polymerase II (RPB3) with transcription factor-4 (ATF4). |
| GO:0005515 protein binding | IPI PMID:16169070 A human protein-protein interaction network: a resource for ... | MARK AS OVER ANNOTATED | Summary: High-throughput interaction study. Generic protein binding annotation from large-scale study. Reason: Generic protein binding from HT study lacks functional specificity. Supporting Evidence: PMID:16169070 A human protein-protein interaction network: a resource for annotating the proteome. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: High-throughput Y2H study. Generic protein binding annotation. Reason: Generic protein binding from HT study lacks functional context. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0005515 protein binding | IPI PMID:16343488 Cooperative interaction of Zhangfei and ATF4 in transactivat... | MODIFY | Summary: Interaction with CREBZF (Zhangfei). Cooperative transactivation of CRE. Reason: This is a specific interaction between bZIP transcription factors. Proposed replacements: leucine zipper domain binding Supporting Evidence: PMID:16343488 2005 Dec 6. Cooperative interaction of Zhangfei and ATF4 in transactivation of the cyclic AMP response element. |
| GO:0005515 protein binding | IPI PMID:18330356 Construction and characterization of a normalized yeast two-... | MARK AS OVER ANNOTATED | Summary: High-throughput Y2H study. Generic protein binding. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:18330356 Construction and characterization of a normalized yeast two-hybrid library derived from a human protein-coding clone collection. |
| GO:0005515 protein binding | IPI PMID:19164757 ERAD inhibitors integrate ER stress with an epigenetic mecha... | MODIFY | Summary: Interaction with ATF3 in the context of ER stress response. Reason: ATF3 is a bZIP transcription factor partner of ATF4. Proposed replacements: leucine zipper domain binding Supporting Evidence: PMID:19164757 ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. |
| GO:0005515 protein binding | IPI PMID:19447967 Shifted Transversal Design smart-pooling for high coverage i... | MARK AS OVER ANNOTATED | Summary: High-throughput interaction mapping study. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:19447967 Shifted Transversal Design smart-pooling for high coverage interactome mapping. |
| GO:0005515 protein binding | IPI PMID:20102225 Identification of bZIP interaction partners of viral protein... | MODIFY | Summary: Coiled-coil array interaction study with viral and cellular bZIP proteins. Reason: These are specific bZIP-bZIP interactions. Proposed replacements: leucine zipper domain binding 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:20211142 An atlas of combinatorial transcriptional regulation in mous... | MARK AS OVER ANNOTATED | Summary: Atlas of transcriptional regulation study. Reason: Generic protein binding from computational/HT study. Supporting Evidence: PMID:20211142 An atlas of combinatorial transcriptional regulation in mouse and man. |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | MODIFY | Summary: MAP kinase interactome study. Interaction with JUN family. Reason: Interaction with JUN represents bZIP heterodimerization. Proposed replacements: leucine zipper domain binding Supporting Evidence: PMID:20936779 A human MAP kinase interactome. |
| GO:0005515 protein binding | IPI PMID:21408167 New modularity of DAP-kinases: alternative splicing of the D... | MODIFY | Summary: Interaction with DAPK2. ATF4 is a substrate of death-associated protein kinases. Reason: This is a kinase-substrate interaction. Proposed replacements: protein kinase binding Supporting Evidence: PMID:21408167 New modularity of DAP-kinases: alternative splicing of the DRP-1 gene produces a ZIPk-like isoform. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: Liver interactome study. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver. |
| GO:0005515 protein binding | IPI PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... | MODIFY | Summary: Systematic bZIP interaction network study. Documents heterodimerization with multiple bZIP partners. Reason: This study specifically characterizes bZIP-bZIP interactions. Proposed replacements: leucine zipper domain binding Supporting Evidence: PMID:23661758 Networks of bZIP protein-protein interactions diversified over a billion years of evolution. |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | MARK AS OVER ANNOTATED | Summary: Proximity ligation assay study. Reason: Generic protein binding annotation. Supporting Evidence: PMID:25241761 Oct 9. Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Large-scale proteome interactome mapping. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: Study of genetic variant effects on protein interactions. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders. |
| GO:0005515 protein binding | IPI PMID:26700459 Involvement of Nrf2 in proteasome inhibition-mediated induct... | MODIFY | Summary: Interaction with NRF2/NFE2L2 in the context of proteasome inhibition. Reason: ATF4 and NRF2 cooperate in antioxidant response. Proposed replacements: leucine zipper domain binding Supporting Evidence: PMID:26700459 Involvement of Nrf2 in proteasome inhibition-mediated induction of ORP150 in thyroid cancer cells. |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | MARK AS OVER ANNOTATED | Summary: Alternative splicing effects on protein interactions. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | MARK AS OVER ANNOTATED | Summary: Cross-species protein interaction network. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:27107014 An inter-species protein-protein interaction network across vast evolutionary distance. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Large-scale interactome study. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | MARK AS OVER ANNOTATED | Summary: Interactome perturbation study. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:29892012 Jun 11. An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders. |
| GO:0005515 protein binding | IPI PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d... | MODIFY | Summary: Alzheimer's disease interactome study. Interaction with DISC1. Reason: DISC1 interaction is functionally relevant for ATF4 regulation. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's disease. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Genetic variant effects on protein interactions. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Large-scale binary interactome mapping. Reason: Generic protein binding from HT 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 ... | MARK AS OVER ANNOTATED | Summary: Neurodegenerative disease protein interactome. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:32911434 A functionally defined high-density NRF2 interactome reveals... | MODIFY | Summary: NRF2 interactome study. ATF4-NRF2 cooperation in antioxidant response. Reason: Functional interaction between ATF4 and NRF2. Proposed replacements: leucine zipper domain binding Supporting Evidence: PMID:32911434 Aug 20. A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Cell-specific interactome remodeling study. Reason: Generic protein binding from HT study. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:9488481 ZIP kinase, a novel serine/threonine kinase which mediates a... | MODIFY | Summary: Interaction with ZIP kinase (DAPK3). ATF4 is phosphorylated by DAPK3. Reason: This is a kinase-substrate interaction. Proposed replacements: protein kinase binding Supporting Evidence: PMID:9488481 ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. |
| GO:0042802 identical protein binding | IPI PMID:16343488 Cooperative interaction of Zhangfei and ATF4 in transactivat... | ACCEPT | Summary: ATF4 can form homodimers through its leucine zipper domain. Reason: ATF4 homodimerization is documented and functionally relevant for DNA binding. Supporting Evidence: PMID:16343488 2005 Dec 6. Cooperative interaction of Zhangfei and ATF4 in transactivation of the cyclic AMP response element. |
| GO:0042802 identical protein binding | IPI PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... | ACCEPT | Summary: ATF4 homodimerization confirmed in systematic bZIP interaction study. Reason: Confirms homodimerization capability. Supporting Evidence: PMID:23661758 Networks of bZIP protein-protein interactions diversified over a billion years of evolution. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 can act as a transcriptional repressor in certain contexts, particularly for memory formation in neurons. Reason: While ATF4 can repress transcription (e.g., long-term memory genes), its primary role is as a transcriptional activator in the ISR. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 binds to CRE and CARE/AARE sequences in pol II-transcribed genes. Reason: Core molecular function of ATF4. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 is a pol II transcription factor. Reason: Core molecular function. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 primarily functions as a transcriptional activator. Reason: Core molecular function supported by experimental evidence. |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 forms complexes with other transcription factors. Reason: ATF4 forms heterodimeric complexes with other bZIP factors. |
| GO:0007214 gamma-aminobutyric acid signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Based on rat ortholog. ATF4 interacts with GABA-B receptors in neurons. Reason: This is a specialized neuronal function, not the core ISR role. |
| GO:0007623 circadian rhythm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 can regulate circadian gene expression via CRE binding. Reason: Circadian regulation is a secondary function. |
| GO:0008140 cAMP response element binding protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 heterodimerizes with CREB family members. Reason: Documented interaction with CREB1 (PMID:12871976). Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:0009636 response to toxic substance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 is activated by various cellular stresses including toxic insults. Reason: General stress response, not specific to toxicants. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 positively regulates stress-responsive genes. Reason: Core function as transcriptional activator. |
| GO:0030182 neuron differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Based on rat ortholog data. Reason: Specialized developmental function, not core ISR role. |
| GO:0030282 bone mineralization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 regulates osteoblast differentiation and bone formation. Reason: Important physiological function but secondary to ISR role (PMID:15109498). Supporting Evidence: PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 is a key effector of the PERK branch of the UPR during ER stress. Reason: Core function of ATF4 in the ISR/UPR (PMID:12871976, PMID:33384352). Supporting Evidence: PMID:33384352 QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis. |
| GO:0032590 dendrite membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Based on rat ortholog. Relates to GABA-B receptor interaction in neurons. Reason: Specialized neuronal localization. |
| GO:0032922 circadian regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 binds CRE elements in clock gene promoters. Reason: Secondary function. |
| GO:0034198 cellular response to amino acid starvation | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 is translationally induced during amino acid deprivation via GCN2-eIF2alpha pathway. Reason: Core function - ATF4 is the central transcription factor activated during amino acid starvation (PMID:11960987). Supporting Evidence: PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000120 | ACCEPT | Summary: ATF4 regulates antioxidant gene expression in response to oxidative stress. Reason: ATF4 activates genes involved in redox homeostasis as part of the ISR. |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 is the key transcription factor downstream of PERK during ER stress. Reason: Core function (PMID:12871976, PMID:33384352). |
| GO:0035162 embryonic hemopoiesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Based on mouse knockout phenotype. Reason: Developmental function, not core ISR role. |
| GO:0035497 cAMP response element binding | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 binds CRE sequences. Reason: Core molecular function of ATF4 as a bZIP transcription factor. |
| GO:0036499 PERK-mediated unfolded protein response | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 is the key transcription factor downstream of PERK. Reason: Core function (PMID:31023583, PMID:12871976). Supporting Evidence: PMID:31023583 2019 Apr 22. ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2Ξ± Axis. |
| GO:0042789 mRNA transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 regulates pol II transcription. Reason: Core function. |
| GO:0043267 negative regulation of potassium ion transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Based on rat ortholog. Specialized neuronal function. Reason: Specialized neuronal function. |
| GO:0043525 positive regulation of neuron apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 with CHOP can promote neuronal apoptosis during prolonged stress. Reason: Context-dependent pro-apoptotic function during chronic stress. |
| GO:0045667 regulation of osteoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 is required for osteoblast differentiation. Reason: Important developmental function but not core ISR role (PMID:15109498). |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 activates transcription of stress-responsive genes. Reason: Core function. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 activates pol II-mediated transcription. Reason: Core function. |
| GO:0046982 protein heterodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 heterodimerizes with other bZIP transcription factors via its leucine zipper domain. Reason: Core molecular function for DNA binding (PMID:12871976, PMID:18940792). Supporting Evidence: PMID:18940792 2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. |
| GO:0048167 regulation of synaptic plasticity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 acts as a memory suppressor in neurons. Reason: Specialized neuronal function. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 with CHOP activates pro-apoptotic genes during prolonged ER stress. Reason: Context-dependent function during chronic stress, not the primary adaptive role. |
| GO:0070309 lens fiber cell morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Based on mouse knockout phenotype. Reason: Developmental function. |
| GO:0071456 cellular response to hypoxia | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 is stabilized under hypoxia via reduced hydroxylation by PHD3. Reason: ATF4 is regulated by hypoxia and contributes to hypoxic gene expression. |
| GO:0090575 RNA polymerase II transcription regulator complex | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 forms transcription factor complexes. Reason: ATF4 forms heterodimeric complexes with other bZIP factors. |
| GO:0120163 negative regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 suppresses thermogenic gene expression. Reason: Specialized metabolic function. |
| GO:0140296 general transcription initiation factor binding | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 interacts with general transcription machinery. Reason: Consistent with its function as a transcription factor. |
| GO:0140297 DNA-binding transcription factor binding | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 interacts with other transcription factors. Reason: ATF4 heterodimerizes with other bZIP transcription factors. |
| GO:0140467 integrated stress response signaling | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 is THE central transcription factor of the ISR. Reason: Core function - ATF4 is the master transcription factor effector of the ISR (PMID:32132707). Supporting Evidence: PMID:32132707 Mar 4. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. |
| GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATF4 can be protective against oxidative stress in neurons. Reason: Context-dependent neuroprotective function. |
| GO:1990253 cellular response to leucine starvation | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 is induced by leucine starvation via GCN2. Reason: Core function - amino acid sensing is a primary trigger of ATF4 induction. |
| GO:1990589 ATF4-CREB1 transcription factor complex | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of IBA annotation. Reason: ATF4-CREB1 complex formation is documented. |
| GO:1990590 ATF1-ATF4 transcription factor complex | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of IBA annotation. Reason: ATF4-ATF1 complex formation is documented. |
| GO:1990737 response to manganese-induced endoplasmic reticulum stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Specific stressor that activates ER stress and ATF4. Reason: Specific toxic stressor response. |
| GO:1990841 promoter-specific chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: ATF4 binds to specific promoter sequences. Reason: Core molecular function. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasmic localization confirmed by immunofluorescence. Reason: Consistent with nuclear transcription factor function. |
| GO:0005634 nucleus | NAS PMID:12871976 Induction of Grp78/BiP by translational block: activation of... | ACCEPT | Summary: Nuclear localization discussed in study. Reason: Consistent with transcription factor function. Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:0005634 nucleus | NAS PMID:20102225 Identification of bZIP interaction partners of viral protein... | ACCEPT | Summary: Nuclear localization in bZIP interaction study. Reason: Consistent with transcription factor function. Supporting Evidence: PMID:20102225 Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays. |
| GO:0005634 nucleus | NAS PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... | ACCEPT | Summary: Nuclear localization in bZIP network study. Reason: Consistent with transcription factor function. Supporting Evidence: PMID:23661758 Networks of bZIP protein-protein interactions diversified over a billion years of evolution. |
| GO:0005634 nucleus | NAS PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specif... | ACCEPT | Summary: Nuclear localization discussed. Reason: Consistent with transcription factor function. Supporting Evidence: PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specificity landscapes. |
| GO:0006357 regulation of transcription by RNA polymerase II | NAS PMID:20102225 Identification of bZIP interaction partners of viral protein... | ACCEPT | Summary: Transcriptional regulation discussed. Reason: Core function. 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:23661758 Networks of bZIP protein-protein interactions diversified ov... | ACCEPT | Summary: Transcriptional regulation discussed. Reason: Core function. Supporting Evidence: PMID:23661758 Networks of bZIP protein-protein interactions diversified over a billion years of evolution. |
| GO:0006357 regulation of transcription by RNA polymerase II | NAS PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specif... | ACCEPT | Summary: Transcriptional regulation discussed. Reason: Core function. Supporting Evidence: PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specificity landscapes. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:16343488 Cooperative interaction of Zhangfei and ATF4 in transactivat... | ACCEPT | Summary: ATF4 with Zhangfei cooperatively activates CRE-driven transcription. Reason: Direct experimental evidence for transcriptional activation. Supporting Evidence: PMID:16343488 2005 Dec 6. Cooperative interaction of Zhangfei and ATF4 in transactivation of the cyclic AMP response element. |
| GO:0140467 integrated stress response signaling | NAS PMID:28566324 Multi-omics analysis identifies ATF4 as a key regulator of t... | ACCEPT | Summary: ATF4 as key regulator of mitochondrial stress response. Reason: Core function in ISR. Supporting Evidence: PMID:28566324 2017 May 31. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:31023583 ER and Nutrient Stress Promote Assembly of Respiratory Chain... | ACCEPT | Summary: ATF4 transcription factor activity demonstrated in PERK-eIF2alpha axis study. Reason: Core molecular function. Supporting Evidence: PMID:31023583 2019 Apr 22. ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2Ξ± Axis. |
| GO:0036499 PERK-mediated unfolded protein response | IDA PMID:31023583 ER and Nutrient Stress Promote Assembly of Respiratory Chain... | ACCEPT | Summary: ATF4 mediates PERK-dependent transcription. Reason: Core function. Supporting Evidence: PMID:31023583 2019 Apr 22. ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2Ξ± Axis. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:23123191 Functional interaction of protein kinase CK2 and activating ... | ACCEPT | Summary: ATF4 transcription factor activity demonstrated, regulated by CK2 phosphorylation. Reason: Core molecular function. Supporting Evidence: PMID:23123191 Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: ATF4 transcription factor activity in mitochondrial stress response. Reason: Core molecular function. Supporting Evidence: PMID:32132707 Mar 4. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: ATF4 is downstream of HRI in mitochondrial stress signaling. Reason: Core function - ATF4 is activated by HRI during mitochondrial stress via DELE1. Supporting Evidence: PMID:32132706 Mar 4. A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. |
| GO:0034599 cellular response to oxidative stress | IMP PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | ACCEPT | Summary: ATF4 mediates transcriptional response to oxidative stress in neurons. Reason: Core function in stress response. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:12871976 Induction of Grp78/BiP by translational block: activation of... | ACCEPT | Summary: ATF4 activates GRP78/BiP promoter during ER stress. Reason: Core function. Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:0034976 response to endoplasmic reticulum stress | IMP PMID:21113145 Parkin is transcriptionally regulated by ATF4: evidence for ... | ACCEPT | Summary: ATF4 transcriptionally regulates parkin during ER stress. Reason: Core function. Supporting Evidence: PMID:21113145 Nov 26. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12871976 Induction of Grp78/BiP by translational block: activation of... | ACCEPT | Summary: ATF4 activates GRP78/BiP transcription. Reason: Core function. Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:21113145 Parkin is transcriptionally regulated by ATF4: evidence for ... | ACCEPT | Summary: ATF4 activates parkin transcription. Reason: Core function. Supporting Evidence: PMID:21113145 Nov 26. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | ACCEPT | Summary: Based on rat ortholog study of neuroprotection. Reason: Consistent with core function. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas... | ACCEPT | Summary: ATF4 activates DR5 transcription during ER stress. Reason: Core function. Supporting Evidence: PMID:24939851 2014 Jun 17. Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib. |
| GO:0034599 cellular response to oxidative stress | IMP PMID:21113145 Parkin is transcriptionally regulated by ATF4: evidence for ... | ACCEPT | Summary: ATF4 mediates oxidative stress response. Reason: Core function. Supporting Evidence: PMID:21113145 Nov 26. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. |
| GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IGI PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | KEEP AS NON CORE | Summary: ATF4 protects neurons against oxidative stress-induced apoptosis. Reason: Specialized neuroprotective function. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | TAS PMID:14685163 Roles of CHOP/GADD153 in endoplasmic reticulum stress. | ACCEPT | Summary: Review discusses ATF4 transcriptional activation with CHOP. Reason: Core function. Supporting Evidence: PMID:14685163 Roles of CHOP/GADD153 in endoplasmic reticulum stress. |
| GO:1990253 cellular response to leucine starvation | IDA PMID:17267404 ATF2 is required for amino acid-regulated transcription by o... | ACCEPT | Summary: ATF4 binds chromatin during amino acid starvation. Reason: Core function in amino acid sensing. Supporting Evidence: PMID:17267404 ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation. |
| GO:1990841 promoter-specific chromatin binding | IDA PMID:17267404 ATF2 is required for amino acid-regulated transcription by o... | ACCEPT | Summary: ATF4 chromatin binding demonstrated by ChIP. Reason: Core molecular function. Supporting Evidence: PMID:17267404 ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:33384352 QRICH1 dictates the outcome of ER stress through transcripti... | ACCEPT | Summary: ATF4 cooperates with QRICH1 in ER stress response. Reason: Core function. Supporting Evidence: PMID:33384352 QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis. |
| GO:0140467 integrated stress response signaling | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: ATF4 is the key effector of the ISR. Reason: Core function. Supporting Evidence: PMID:32132707 Mar 4. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: ATF4 downstream of HRI in mitochondrial stress. Reason: Core function. Supporting Evidence: PMID:32132707 Mar 4. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: ATF4 DNA binding specificity characterized, including methylation sensitivity. Reason: Core molecular function. Supporting Evidence: PMID:28473536 Impact of cytosine methylation on DNA binding specificities of human transcription factors. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATF4 can repress transcription in certain contexts. Reason: ATF4 primarily activates transcription; repression is context-dependent. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... | ACCEPT | Summary: ATF4 transcription factor activity in nutrient sensing. Reason: Core molecular function. Supporting Evidence: PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of os... | ACCEPT | Summary: ATF4 transcription factor activity in osteoblast differentiation. Reason: Core molecular function. Supporting Evidence: PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. |
| GO:0005515 protein binding | IPI PMID:23123191 Functional interaction of protein kinase CK2 and activating ... | MODIFY | Summary: ATF4 interacts with CK2 as a substrate. Reason: This is a kinase-substrate interaction. Proposed replacements: protein kinase binding Supporting Evidence: PMID:23123191 Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response. |
| GO:0005634 nucleus | IDA PMID:23123191 Functional interaction of protein kinase CK2 and activating ... | ACCEPT | Summary: Nuclear localization of ATF4-CK2 interaction. Reason: Core localization. Supporting Evidence: PMID:23123191 Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response. |
| GO:0008140 cAMP response element binding protein binding | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 interacts with CREB family members. Reason: Documented interaction. |
| GO:0030282 bone mineralization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATF4 regulates bone mineralization via osteoblast function. Reason: Physiological function but not core ISR role. |
| GO:0030968 endoplasmic reticulum unfolded protein response | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 is a key UPR effector. Reason: Core function. |
| GO:0031667 response to nutrient levels | IDA PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... | ACCEPT | Summary: ATF4 mediates transcriptional response to nutrient deprivation. Reason: Core function in nutrient sensing. Supporting Evidence: PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. |
| GO:0034599 cellular response to oxidative stress | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 mediates oxidative stress response. Reason: Core function. |
| GO:0035162 embryonic hemopoiesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Based on mouse knockout phenotype. Reason: Developmental function. |
| GO:0036499 PERK-mediated unfolded protein response | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 downstream of PERK. Reason: Core function. |
| GO:0045667 regulation of osteoblast differentiation | IDA PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of os... | KEEP AS NON CORE | Summary: ATF4 is required for osteoblast differentiation. Reason: Important but not core ISR function. Supporting Evidence: PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... | ACCEPT | Summary: ATF4 activates ASNS transcription. Reason: Core function. Supporting Evidence: PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of os... | ACCEPT | Summary: ATF4 activates osteoblast gene transcription. Reason: Core function. Supporting Evidence: PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:23123191 Functional interaction of protein kinase CK2 and activating ... | ACCEPT | Summary: ATF4 transcriptional activity regulated by CK2. Reason: Core function. Supporting Evidence: PMID:23123191 Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response. |
| GO:0046982 protein heterodimerization activity | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 heterodimerizes with bZIP partners. Reason: Core molecular function. |
| GO:0048167 regulation of synaptic plasticity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATF4 regulates memory-related genes. Reason: Specialized neuronal function. |
| GO:0070309 lens fiber cell morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Based on mouse knockout phenotype. Reason: Developmental function. |
| GO:0070982 L-asparagine metabolic process | IDA PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... | ACCEPT | Summary: ATF4 activates asparagine synthetase (ASNS) gene transcription. Reason: Core target gene regulation. Supporting Evidence: PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. |
| GO:0010628 positive regulation of gene expression | IMP PMID:16445384 Characterization of the amino acid response element within t... | ACCEPT | Summary: ATF4 regulates SNAT2 expression. Reason: Core function in amino acid transporter regulation. Supporting Evidence: PMID:16445384 Characterization of the amino acid response element within the human sodium-coupled neutral amino acid transporter 2 (SNAT2) System A transporter gene. |
| GO:0003677 DNA binding | IDA PMID:15911876 FIAT represses ATF4-mediated transcription to regulate bone ... | ACCEPT | Summary: ATF4 DNA binding activity demonstrated. Reason: Core molecular function. Supporting Evidence: PMID:15911876 FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: ATF4 binds chromatin as a transcription factor. Reason: Consistent with transcription factor function. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: ATF4 is a pol II transcription factor. Reason: Core molecular function. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:12871976 Induction of Grp78/BiP by translational block: activation of... | ACCEPT | Summary: ATF4 transcription factor activity demonstrated. Reason: Core molecular function. Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:0120163 negative regulation of cold-induced thermogenesis | ISS PMID:22980225 Effects of ATF4 on PGC1Ξ± expression in brown adipose tissue ... | KEEP AS NON CORE | Summary: ATF4 suppresses thermogenic gene expression. Reason: Specialized metabolic function. Supporting Evidence: PMID:22980225 2012 Sep 11. Effects of ATF4 on PGC1Ξ± expression in brown adipose tissue and metabolic responses to cold stress. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 binds CRE sequences. Reason: Core molecular function. |
| GO:0005813 centrosome | IDA PMID:20873783 Characterization of hNek6 interactome reveals an important r... | KEEP AS NON CORE | Summary: ATF4 localizes to centrosome with NEK6. Reason: Non-canonical localization, not central to ISR function. Supporting Evidence: PMID:20873783 Oct 22. Characterization of hNek6 interactome reveals an important role for its short N-terminal domain and colocalization with proteins at the centrosome. |
| GO:0019901 protein kinase binding | IPI PMID:20873783 Characterization of hNek6 interactome reveals an important r... | ACCEPT | Summary: ATF4 interacts with NEK6 kinase. Reason: Documented kinase interaction. Supporting Evidence: PMID:20873783 Oct 22. Characterization of hNek6 interactome reveals an important role for its short N-terminal domain and colocalization with proteins at the centrosome. |
| GO:0032991 protein-containing complex | IDA PMID:20873783 Characterization of hNek6 interactome reveals an important r... | ACCEPT | Summary: ATF4 forms protein complexes. Reason: Consistent with bZIP dimerization. Supporting Evidence: PMID:20873783 Oct 22. Characterization of hNek6 interactome reveals an important role for its short N-terminal domain and colocalization with proteins at the centrosome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796061 | ACCEPT | Summary: ATF4 is synthesized in the cytosol. Reason: ATF4 is translated in the cytoplasm. |
| GO:0005634 nucleus | IDA PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | ACCEPT | Summary: Nuclear localization in Parkinson's disease model. Reason: Core localization. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0032057 negative regulation of translational initiation in response to stress | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATF4 is part of the translation regulation pathway via ISR. Reason: ATF4 is a consequence of translation regulation, not a direct regulator of translation initiation. |
| GO:0034644 cellular response to UV | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 is induced by UV stress. Reason: Part of general stress response. |
| GO:0034198 cellular response to amino acid starvation | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 is induced by amino acid starvation. Reason: Core function. |
| GO:0042789 mRNA transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 regulates pol II transcription. Reason: Core function. |
| GO:0036499 PERK-mediated unfolded protein response | TAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | ACCEPT | Summary: ATF4 downstream of PERK discussed in review. Reason: Core function. Supporting Evidence: PMID:22934019 The endoplasmic reticulum stress response in aging and age-related diseases. |
| GO:0034976 response to endoplasmic reticulum stress | IMP PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas... | ACCEPT | Summary: ATF4 mediates ER stress response. Reason: Core function. Supporting Evidence: PMID:24939851 2014 Jun 17. Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib. |
| GO:0036499 PERK-mediated unfolded protein response | TAS PMID:22013210 The unfolded protein response: integrating stress signals th... | ACCEPT | Summary: ATF4 downstream of PERK in UPR. Reason: Core function. Supporting Evidence: PMID:22013210 The unfolded protein response: integrating stress signals through the stress sensor IRE1Ξ±. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... | ACCEPT | Summary: ATF4 transcription factor activity with CHOP. Reason: Core molecular function. Supporting Evidence: PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP). |
| GO:0043522 leucine zipper domain binding | IDA PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... | ACCEPT | Summary: ATF4 interacts with CHOP via leucine zipper. Reason: Core molecular function for bZIP heterodimerization. Supporting Evidence: PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP). |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... | ACCEPT | Summary: ATF4 interacts with CHOP transcription factor. Reason: Core molecular function. Supporting Evidence: PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP). |
| GO:1990617 CHOP-ATF4 complex | IDA PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... | ACCEPT | Summary: ATF4-CHOP complex formation demonstrated. Reason: Important transcription factor complex in stress response. Supporting Evidence: PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP). |
| GO:0005634 nucleus | IDA PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... | ACCEPT | Summary: Nuclear localization with CHOP. Reason: Core localization. Supporting Evidence: PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP). |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... | ACCEPT | Summary: ATF4-CHOP activates transcription. Reason: Core function. Supporting Evidence: PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP). |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:15775988 TRB3, a novel ER stress-inducible gene, is induced via ATF4-... | ACCEPT | Summary: ATF4-CHOP activates TRB3 transcription. Reason: Core function. Supporting Evidence: PMID:15775988 Mar 10. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... | ACCEPT | Summary: ATF4 activates transcription, regulated by CHOP. Reason: Core function. Supporting Evidence: PMID:18940792 2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. |
| GO:1990617 CHOP-ATF4 complex | NAS PMID:15775988 TRB3, a novel ER stress-inducible gene, is induced via ATF4-... | ACCEPT | Summary: ATF4-CHOP complex discussed. Reason: Important complex. Supporting Evidence: PMID:15775988 Mar 10. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. |
| GO:1990617 CHOP-ATF4 complex | IPI PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... | ACCEPT | Summary: ATF4-CHOP interaction demonstrated. Reason: Important complex. Supporting Evidence: PMID:18940792 2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. |
| GO:1990589 ATF4-CREB1 transcription factor complex | IDA PMID:12871976 Induction of Grp78/BiP by translational block: activation of... | ACCEPT | Summary: ATF4-CREB1 complex demonstrated. Reason: Core transcription factor complex. Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:1990590 ATF1-ATF4 transcription factor complex | IDA PMID:12871976 Induction of Grp78/BiP by translational block: activation of... | ACCEPT | Summary: ATF4-ATF1 complex demonstrated. Reason: Core transcription factor complex. Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:12871976 Induction of Grp78/BiP by translational block: activation of... | ACCEPT | Summary: ATF4 binds to ATF/CRE regulatory sequences. Reason: Core molecular function. Supporting Evidence: PMID:12871976 2003 Jul 18. 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. |
| GO:0010575 positive regulation of vascular endothelial growth factor production | IMP PMID:22915762 The unfolded protein response induces the angiogenic switch ... | KEEP AS NON CORE | Summary: ATF4 induces VEGF during ER stress. Reason: Context-dependent angiogenic function. Supporting Evidence: PMID:22915762 Epub 2012 Aug 20. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. |
| GO:0042149 cellular response to glucose starvation | IMP PMID:22915762 The unfolded protein response induces the angiogenic switch ... | ACCEPT | Summary: ATF4 mediates glucose starvation response. Reason: Part of nutrient stress response. Supporting Evidence: PMID:22915762 Epub 2012 Aug 20. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:22915762 The unfolded protein response induces the angiogenic switch ... | ACCEPT | Summary: ATF4 DNA binding activity. Reason: Core molecular function. Supporting Evidence: PMID:22915762 Epub 2012 Aug 20. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. |
| GO:0045943 positive regulation of transcription by RNA polymerase I | IMP PMID:22915762 The unfolded protein response induces the angiogenic switch ... | UNDECIDED | Summary: ATF4 may regulate pol I transcription. Reason: ATF4 is primarily a pol II transcription factor. Pol I regulation is atypical and needs verification. Supporting Evidence: PMID:22915762 Epub 2012 Aug 20. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:21113145 Parkin is transcriptionally regulated by ATF4: evidence for ... | ACCEPT | Summary: ATF4 binds parkin promoter. Reason: Core molecular function. Supporting Evidence: PMID:21113145 Nov 26. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. |
| GO:0000976 transcription cis-regulatory region binding | TAS PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | ACCEPT | Summary: ATF4 cis-regulatory binding discussed. Reason: Core molecular function. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0005737 cytoplasm | IDA PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | ACCEPT | Summary: Cytoplasmic ATF4 in neurons. Reason: ATF4 can be cytoplasmic before stress-induced nuclear translocation. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0034399 nuclear periphery | IDA PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | KEEP AS NON CORE | Summary: ATF4 at nuclear periphery in neurons. Reason: Specialized neuronal localization. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0043005 neuron projection | IDA PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | KEEP AS NON CORE | Summary: ATF4 in neuron projections. Reason: Specialized neuronal localization. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0043065 positive regulation of apoptotic process | TAS PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | KEEP AS NON CORE | Summary: ATF4 can promote apoptosis during stress. Reason: Context-dependent pro-apoptotic function. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:1990037 Lewy body core | IDA PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... | KEEP AS NON CORE | Summary: ATF4 found in Lewy bodies in Parkinson's disease. Reason: Pathological localization in neurodegeneration. Supporting Evidence: PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. |
| GO:0032922 circadian regulation of gene expression | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATF4 regulates circadian genes. Reason: Secondary function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9635804 | ACCEPT | Summary: ATF4 nucleoplasmic localization in Reactome pathway. Reason: Core localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9635892 | ACCEPT | Summary: ATF4 nucleoplasmic localization. Reason: Core localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9635936 | ACCEPT | Summary: ATF4 nucleoplasmic localization. Reason: Core localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9653893 | ACCEPT | Summary: ATF4 nucleoplasmic localization. Reason: Core localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9761815 | ACCEPT | Summary: ATF4 nucleoplasmic localization. Reason: Core localization. |
| GO:0003677 DNA binding | IDA PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... | ACCEPT | Summary: ATF4 DNA binding demonstrated. Reason: Core molecular function. Supporting Evidence: PMID:18940792 2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. |
| GO:0005515 protein binding | IPI PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... | MODIFY | Summary: ATF4 interacts with CHOP. Reason: This is a specific bZIP-bZIP interaction. Proposed replacements: leucine zipper domain binding Supporting Evidence: PMID:18940792 2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. |
| GO:0043525 positive regulation of neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATF4-CHOP can promote neuronal apoptosis. Reason: Context-dependent, not core function. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... | ACCEPT | Summary: ATF4 activates transcription. Reason: Core function. Supporting Evidence: PMID:18940792 2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATF4-CHOP activate apoptotic pathway during prolonged ER stress. Reason: Context-dependent, chronic stress response. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:15775988 TRB3, a novel ER stress-inducible gene, is induced via ATF4-... | ACCEPT | Summary: ATF4-CHOP activate TRB3 transcription. Reason: Core function. Supporting Evidence: PMID:15775988 Mar 10. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:19061639 Role of SERCA1 truncated isoform in the proapoptotic calcium... | ACCEPT | Summary: ATF4 in ER stress response. Reason: Core function. Supporting Evidence: PMID:19061639 Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. |
| GO:0005515 protein binding | IPI PMID:16682973 The centrosomal protein nephrocystin-6 is mutated in Joubert... | ACCEPT | Summary: ATF4 interacts with CEP290/nephrocystin-6. Reason: Functionally relevant interaction affecting ATF4 activity. Supporting Evidence: PMID:16682973 The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. |
| GO:0005634 nucleus | IDA PMID:16682973 The centrosomal protein nephrocystin-6 is mutated in Joubert... | ACCEPT | Summary: Nuclear localization with CEP290. Reason: Core localization. Supporting Evidence: PMID:16682973 The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. |
| GO:0005515 protein binding | IPI PMID:15677469 Mitosin/CENP-F as a negative regulator of activating transcr... | KEEP AS NON CORE | Summary: ATF4 interacts with mitosin/CENP-F. Reason: Interaction affecting ATF4 regulation but not core function. Supporting Evidence: PMID:15677469 2005 Jan 26. Mitosin/CENP-F as a negative regulator of activating transcription factor-4. |
| GO:0003677 DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 DNA binding. Reason: Core molecular function. |
| GO:0003677 DNA binding | IDA PMID:15788408 The oxidative stressor arsenite activates vascular endotheli... | ACCEPT | Summary: ATF4 DNA binding in arsenite response. Reason: Core molecular function. Supporting Evidence: PMID:15788408 2005 Mar 23. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism. |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:12689582 All roads lead to ATF4. | ACCEPT | Summary: Review of ATF4 as transcription factor. Reason: Core molecular function. Supporting Evidence: PMID:12689582 All roads lead to ATF4. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Nuclear localization. Reason: Core localization. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Cytoplasmic localization. Reason: ATF4 is translated in cytoplasm. |
| GO:0006094 gluconeogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATF4 regulates gluconeogenic genes. Reason: Metabolic function, not core ISR role. |
| GO:0006355 regulation of DNA-templated transcription | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 regulates transcription. Reason: Core function. |
| GO:0006366 transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 in pol II transcription. Reason: Core function. |
| GO:0045893 positive regulation of DNA-templated transcription | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 activates transcription. Reason: Core function. |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... | ACCEPT | Summary: ATF4 activates ASNS transcription. Reason: Core function. Supporting Evidence: PMID:11960987 2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. |
| GO:0045893 positive regulation of DNA-templated transcription | NAS PMID:9190894 Functional interaction of the HTLV-1 transactivator Tax with... | ACCEPT | Summary: ATF4 with HTLV-1 Tax in transcription. Reason: Core function. Supporting Evidence: PMID:9190894 Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4). |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: ATF4 activates pol II transcription. Reason: Core function. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:15788408 The oxidative stressor arsenite activates vascular endotheli... | ACCEPT | Summary: ATF4 activates VEGF transcription. Reason: Core function. Supporting Evidence: PMID:15788408 2005 Mar 23. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: What determines whether ATF4 promotes cell survival (adaptive ISR) versus cell death (terminal UPR/apoptosis)?
Q: How do different bZIP dimerization partners affect ATF4 target gene specificity?
Q: What is the significance of ATF4 localization to the centrosome and its interaction with NEK6?
Experiment: ChIP-seq comparing ATF4 chromatin binding with different stress conditions (ER stress vs amino acid starvation vs mitochondrial stress) to define stress-specific target genes
Hypothesis: Different stressors activate distinct ATF4 target gene programs
Experiment: Time-course proteomics following ATF4 induction to distinguish early adaptive targets from late pro-apoptotic targets
Hypothesis: Temporal dynamics of ATF4 activity determines cell fate
Experiment: CRISPR screens to identify ATF4-dependent genes essential for survival during different stress conditions
Hypothesis: Specific ATF4 target genes are required for stress adaptation
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)