CCNE1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000082 G1/S transition of mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: Core function. Cyclin E1 is the canonical regulator of G1/S transition via CDK2 activation. Extensively supported by phylogenetic inference (IBA) and all literature. Reason: G1/S transition is the defining biological process for cyclin E1. The deep research (CCNE1-deep-research-falcon.md) confirms "Cyclin E1 is a non-enzymatic regulatory subunit whose primary molecular function is to bind and activate CDK2, thereby promoting late G1 progression and G1/S transition" (kasirzadeh2024targetingcdk2to). IBA annotations for such core functions are typically well-reviewed. Supporting Evidence: PMID:15838514 Cyclin E-Cdk2 has long been considered an essential and master regulator of progression through G1 phase of the cell cycle
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Cyclin E1 is a nuclear protein as established by multiple lines of evidence including the UniProt record which states "Nucleus" with experimental evidence from PMID:7739542. Reason: Nuclear localization of cyclin E1 is well established. UniProt states "SUBCELLULAR LOCATION: Nucleus" with experimental evidence. IBA annotation is consistent. Supporting Evidence: PMID:19942931 Mtd expression in proliferating cells colocalized with cyclin E1, a G(1)/S phase cell cycle regulator
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Cyclin E1 is also found in the cytoplasm. IHC studies show both nuclear and cytoplasmic localization, and the deep research notes nucleocytoplasmic shuttling. Reason: Cytoplasmic localization is supported by IHC evidence showing "cytoplasmic cyclin E1 was frequently high (70% high vs 30% low)" in ovarian cancer (lashen2024theclinicopathologicalsignificance). Cyclin E and CDK2 are known to shuttle between nucleus and cytoplasm (chen2025targetingcdk2and). IBA annotation is consistent.
GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function of cyclin E1. It is a non-enzymatic regulatory subunit that binds and activates CDK2, a cyclin-dependent serine/threonine kinase. Reason: This is the defining molecular function of cyclin E1. It does not have kinase activity itself but activates CDK2. PMID:8207080 confirms "Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2." The IBA annotation is at the right level of specificity. Supporting Evidence: PMID:8207080 Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2, which is activated shortly before S-phase entry, thus defining it as a G1 cyclin
GO:0097134 cyclin E1-CDK2 complex	IBA GO_REF:0000033	ACCEPT	Summary: Cyclin E1 is a defining component of the cyclin E1-CDK2 complex. Crystal structure of the complex has been solved (PDB:1W98, PMID:15660127). Reason: UniProt states "Interacts with CDK2 protein kinase to form a serine/threonine kinase holoenzyme complex." Multiple crystal structures confirm this (PDB:1W98). ComplexPortal entry CPX-2015 explicitly defines the Cyclin E1-CDK2 complex.
GO:0005815 microtubule organizing center	IBA GO_REF:0000033	ACCEPT	Summary: Cyclin E-CDK2 is known to play a role in centrosome duplication, and localization to centrosomes (microtubule organizing centers) has been reported in the literature for cyclin E in model organisms. The IBA annotation reflects phylogenetic inference from orthologs. Reason: Cyclin E-CDK2 activity is required for centrosome duplication, and cyclin E has been shown to localize to centrosomes. This is supported by the broader cell cycle biology literature and is phylogenetically conserved (IBA).
GO:1900087 positive regulation of G1/S transition of mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: Cyclin E1 positively regulates G1/S transition by activating CDK2, which phosphorylates RB1 to release E2F transcription factors for S-phase gene expression. Reason: This is a core function. The deep research confirms "CDK2-cyclin E activity promotes S-phase entry in large part by phosphorylating RB, enabling E2F transcriptional activation" (kasirzadeh2024targetingcdk2to). The IBA annotation is at the right level of specificity. Supporting Evidence: PMID:15838514 Cyclin E-Cdk2 has long been considered an essential and master regulator of progression through G1 phase of the cell cycle
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for nuclear localization, consistent with the IBA and IDA annotations for the same term. Reason: Redundant with IBA and IDA annotations but not wrong. Nuclear localization is well established for cyclin E1.
GO:0051301 cell division	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. Cell division is a broad term that encompasses the G1/S transition role of cyclin E1. Reason: While broader than the more specific G1/S transition annotations, this IEA is not wrong. Cyclin E1 is clearly involved in cell division. The UniProt record includes "Cell cycle; Cell division" as keywords.
GO:0005515 protein binding	IPI PMID:10330164 Specificity of cyclin E-Cdk2, TFIIB, and E1A interactions wi...	MARK AS OVER ANNOTATED	Summary: Interaction with p300 coactivator. PMID:10330164 shows cyclin E-Cdk2 binds to the COOH-terminal region of p300, though this is described as a complex interaction (cyclin E-Cdk2 rather than cyclin E alone). Reason: The term "protein binding" is uninformative. The actual finding is a specific interaction of cyclin E-Cdk2 complex with the p300 coactivator. However, the GO guidelines discourage generic protein binding annotations. Supporting Evidence: PMID:10330164 the COOH-terminal region of p300 binds to cyclin E-cyclin-dependent kinase 2 (cyclin E-Cdk2) and TFIIB
GO:0005515 protein binding	IPI PMID:11533444 Phosphorylation-dependent ubiquitination of cyclin E by the ...	MARK AS OVER ANNOTATED	Summary: Interaction with FBXW7 (SCFFbw7) for phosphorylation-dependent ubiquitination. This is a well-characterized substrate-E3 ligase interaction. Reason: The term "protein binding" is uninformative. The actual interaction is between cyclin E and FBXW7 as part of SCF-mediated ubiquitination. This is better captured by other annotations related to cyclin E degradation. Supporting Evidence: PMID:11533444 Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase
GO:0005515 protein binding	IPI PMID:16223725 The loss of PIN1 deregulates cyclin E and sensitizes mouse e...	MARK AS OVER ANNOTATED	Summary: Interaction with PIN1 prolyl isomerase. PIN1 regulates cyclin E stability. Reason: Generic protein binding is uninformative. The actual finding is PIN1 regulation of cyclin E stability. Supporting Evidence: PMID:16223725 The loss of PIN1 deregulates cyclin E and sensitizes mouse embryo fibroblasts to genomic instability
GO:0005515 protein binding	IPI PMID:16431923 The nucleocapsid protein of severe acute respiratory syndrom...	MARK AS OVER ANNOTATED	Summary: Interaction with SARS-CoV nucleocapsid protein, which inhibits cyclin-CDK activity. This is a viral pathogen interaction, not a core function. Reason: Generic protein binding is uninformative. The interaction is with a viral protein (SARS-CoV nucleocapsid) and represents pathogen interference with cell cycle, not a core function of cyclin E1. Supporting Evidence: PMID:16431923 The nucleocapsid protein of severe acute respiratory syndrome-coronavirus inhibits the activity of cyclin-cyclin-dependent kinase complex and blocks S phase progression in mammalian cells
GO:0005515 protein binding	IPI PMID:16504183 Regulation of the transcription factor FOXM1c by Cyclin E/CD...	MARK AS OVER ANNOTATED	Summary: Interaction with FOXM1c transcription factor, regulated by Cyclin E/CDK2. UniProt lists FOXM1 as an interaction partner. Reason: Generic protein binding is uninformative. The actual finding is regulation of FOXM1c by cyclin E/CDK2 complex phosphorylation. Supporting Evidence: PMID:16504183 Regulation of the transcription factor FOXM1c by Cyclin E/CDK2
GO:0005515 protein binding	IPI PMID:16721056 G1/S Cyclins interact with regulatory subunit of PKA via A-k...	MARK AS OVER ANNOTATED	Summary: Interaction with AKAP95 (A-kinase anchoring protein). G1/S cyclins interact with PKA regulatory subunit via AKAP95. Reason: Generic protein binding is uninformative. UniProt lists AKAP8 as an interaction partner. Supporting Evidence: PMID:16721056 G1/S Cyclins interact with regulatory subunit of PKA via A-kinase anchoring protein, AKAP95
GO:0005515 protein binding	IPI PMID:16765349 Increased p21 expression and complex formation with cyclin E...	MARK AS OVER ANNOTATED	Summary: Interaction with p21 (CDKN1A) in retinoid-induced apoptosis. p21 is a well-known CDK inhibitor that forms complexes with cyclin E/CDK2. Reason: Generic protein binding is uninformative. The cyclin E-CDK2-p21 interaction is a core regulatory mechanism but should be annotated more specifically. UniProt lists CDKN1A with 11 experiments. Supporting Evidence: PMID:16765349 Increased p21 expression and complex formation with cyclin E/CDK2 in retinoid-induced pre-B lymphoma cell apoptosis
GO:0005515 protein binding	IPI PMID:17254966 Cdk-inhibitory activity and stability of p27Kip1 are directl...	MARK AS OVER ANNOTATED	Summary: Interaction with p27Kip1 (CDKN1B). This is a key CDK inhibitor that regulates cyclin E-CDK2 activity. Reason: Generic protein binding is uninformative. The cyclin E-CDK2-p27 interaction is well characterized. UniProt lists CDKN1B with 12 experiments. Supporting Evidence: PMID:17254966 Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases
GO:0005515 protein binding	IPI PMID:17254967 p27 phosphorylation by Src regulates inhibition of cyclin E-...	MARK AS OVER ANNOTATED	Summary: Another study on p27-cyclin E-Cdk2 interaction, showing Src-dependent phosphorylation of p27 regulates inhibition of cyclin E-Cdk2. Reason: Generic protein binding is uninformative. This is the same well-characterized p27-cyclin E-CDK2 interaction. Supporting Evidence: PMID:17254967 p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2
GO:0005515 protein binding	IPI PMID:17525332 ATM and ATR substrate analysis reveals extensive protein net...	MARK AS OVER ANNOTATED	Summary: Large-scale ATM/ATR substrate analysis. This is a high-throughput study identifying proteins in DNA damage response networks, not a focused study on cyclin E function. Reason: Generic protein binding from a high-throughput study. Does not provide specific information about cyclin E1 function. Supporting Evidence: PMID:17525332 ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage
GO:0005515 protein binding	IPI PMID:19470470 RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA ...	MARK AS OVER ANNOTATED	Summary: Study on RSK1-p27Kip1 phosphorylation. Cyclin E is mentioned as a binding partner of p27 but the study focuses on RSK1 function. Reason: Generic protein binding is uninformative. The study focuses on RSK1 regulation of p27, with cyclin E as a known interactor. Supporting Evidence: PMID:19470470 RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility
GO:0005515 protein binding	IPI PMID:21092281 HTLV-I p30 inhibits multiple S phase entry checkpoints, decr...	MARK AS OVER ANNOTATED	Summary: HTLV-I p30 decreases cyclin E-CDK2 interactions. This is a viral interference study. Reason: Generic protein binding is uninformative. This describes viral pathogen interference with cyclin E-CDK2, not a core function. Supporting Evidence: PMID:21092281 HTLV-I p30 inhibits multiple S phase entry checkpoints, decreases cyclin E-CDK2 interactions and delays cell cycle progression
GO:0005515 protein binding	IPI PMID:21952639 NIRF constitutes a nodal point in the cell cycle network and...	MARK AS OVER ANNOTATED	Summary: Interaction with UHRF2 (NIRF), which ubiquitinates cyclin E1. UniProt confirms this interaction with 4 experiments. Reason: Generic protein binding is uninformative. The actual interaction is a substrate-E3 ligase relationship where UHRF2 ubiquitinates cyclin E1. UniProt states "Interacts directly with UHRF2; the interaction ubiquitinates CCNE1." Supporting Evidence: PMID:21952639 the ubiquitin ligase NIRF (also known as UHRF2), which induces G1 arrest, interacts with multiple cell cycle proteins including cyclins (A2, B1, D1 and E1), p53 and pRB, and ubiquitinates cyclins D1 and E1
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: High-throughput protein interaction study of the human liver. Not a focused study on cyclin E1 function. Reason: Generic protein binding from a large-scale interactome study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver
GO:0005515 protein binding	IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein...	MARK AS OVER ANNOTATED	Summary: Large-scale AP-MS reproducibility study. Not a focused study on cyclin E1. Reason: Generic protein binding from a high-throughput methods study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:23455922 Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS
GO:0005515 protein binding	IPI PMID:23602568 The protein interaction landscape of the human CMGC kinase g...	MARK AS OVER ANNOTATED	Summary: CMGC kinase group interactome study. CDK2 is a CMGC kinase, so cyclin E1 would be identified as an interactor. Reason: Generic protein binding from a kinase interactome study. The cyclin E-CDK2 interaction is already well captured by more specific annotations. Supporting Evidence: PMID:23602568 The protein interaction landscape of the human CMGC kinase group
GO:0005515 protein binding	IPI PMID:23853094 Foxp3 protein stability is regulated by cyclin-dependent kin...	MARK AS OVER ANNOTATED	Summary: Foxp3 stability regulation by CDK2. The study shows CDK2 phosphorylates Foxp3, with cyclin E as the activating partner. Reason: Generic protein binding is uninformative. The actual biology is CDK2 phosphorylation of Foxp3, where cyclin E1 is the activating cyclin partner. Supporting Evidence: PMID:23853094 Foxp3 protein stability is regulated by cyclin-dependent kinase 2
GO:0005515 protein binding	IPI PMID:24358021 Polycomb protein SCML2 regulates the cell cycle by binding a...	MARK AS OVER ANNOTATED	Summary: SCML2 binding to CDK/CYCLIN/p21 complexes. Cyclin E is one of the cyclins in such complexes. Reason: Generic protein binding is uninformative. The study describes SCML2 modulating CDK/cyclin/p21 complexes, with cyclin E as one component. Supporting Evidence: PMID:24358021 Polycomb protein SCML2 regulates the cell cycle by binding and modulating CDK/CYCLIN/p21 complexes
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MARK AS OVER ANNOTATED	Summary: In situ proximity ligation assay (PLA) study for profiling endogenous protein-protein interactions. Reason: Generic protein binding from a methods-focused study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:25241761 Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network
GO:0005515 protein binding	IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo...	MARK AS OVER ANNOTATED	Summary: Kinase network analysis in TRAIL-induced apoptosis. High-throughput study. Reason: Generic protein binding from a high-throughput network analysis study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Large-scale human interactome architecture study. Reason: Generic protein binding from a large-scale interactome study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Binary protein interactome reference map. Reason: Generic protein binding from a large-scale interactome mapping study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Dual proteome-scale interactome study showing cell-specific remodeling. Reason: Generic protein binding from a large-scale interactome study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome
GO:0005515 protein binding	IPI PMID:34591612 A protein interaction landscape of breast cancer.	MARK AS OVER ANNOTATED	Summary: Protein interaction landscape of breast cancer. Reason: Generic protein binding from a tissue-specific interactome study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:34591612 A protein interaction landscape of breast cancer
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: OpenCell endogenous tagging and cartography study. Reason: Generic protein binding from a large-scale cellular organization study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:35271311 OpenCell: Endogenous tagging for the cartography of human cellular organization
GO:0005515 protein binding	IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei...	MARK AS OVER ANNOTATED	Summary: Mutation-directed neo-protein-protein interactions in cancer. Reason: Generic protein binding from a high-throughput cancer study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:35512704 Systematic discovery of mutation-directed neo-protein-protein interactions in cancer
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Multimodal cell maps study. Reason: Generic protein binding from a large-scale cellular mapping study. Uninformative for cyclin E1 functional annotation. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics
GO:0005515 protein binding	IPI PMID:8553588 Human papillomavirus E7 oncoproteins bind a single form of c...	MARK AS OVER ANNOTATED	Summary: HPV E7 oncoproteins bind cyclin E in a complex with CDK2 and p107. This represents viral oncogene interaction with the cyclin E-CDK2 complex. Reason: Generic protein binding is uninformative. The actual finding involves viral E7 oncoprotein binding to cyclin E-CDK2-p107 complexes, which is a pathogen interaction, not a core function. Supporting Evidence: PMID:8553588 Human papillomavirus E7 oncoproteins bind a single form of cyclin E in a complex with cdk2 and p107
GO:0005515 protein binding	IPI PMID:8756624 Cyclin-binding motifs are essential for the function of p21C...	MARK AS OVER ANNOTATED	Summary: Cyclin-binding motifs essential for p21CIP1 function. This demonstrates the p21-cyclin E interaction is functionally important. Reason: Generic protein binding is uninformative. The study reveals specific cyclin-binding motifs in p21, but the annotation should be more specific than "protein binding." Supporting Evidence: PMID:8756624 Cyclin-binding motifs are essential for the function of p21CIP1
GO:0005515 protein binding	IPI PMID:9840943 Cyclin E2, a novel human G1 cyclin and activating partner of...	MARK AS OVER ANNOTATED	Summary: Cyclin E2 discovery paper that also characterizes cyclin E1 interactions with CDK2 and CDK3. Reason: Generic protein binding is uninformative. The CDK2 interaction is already captured by the more specific cyclin E1-CDK2 complex annotation (GO:0097134). Supporting Evidence: PMID:9840943 Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and CDK3, is induced by viral oncoproteins
GO:0000307 cyclin-dependent protein kinase holoenzyme complex	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for CDK holoenzyme complex membership. This is a more general parent of cyclin E1-CDK2 complex (GO:0097134). Reason: While more general than GO:0097134 (cyclin E1-CDK2 complex), this IEA annotation is not wrong. Cyclin E1 is indeed a component of a cyclin-dependent protein kinase holoenzyme complex (the CDK2 holoenzyme). It is acceptable for IEA annotations to be broader.
GO:0016301 kinase activity	IEA GO_REF:0000107	REMOVE	Summary: IEA annotation attributing kinase activity to cyclin E1. However, cyclin E1 is NOT a kinase; it is a regulatory subunit that activates CDK2. Reason: Cyclin E1 does not have kinase activity itself. It is a non-enzymatic regulatory subunit that binds and activates CDK2. PMID:8207080 confirms "Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2." The kinase activity belongs to CDK2, not cyclin E1. The correct MF annotation is GO:0016538 (cyclin-dependent protein serine/threonine kinase regulator activity), which is already annotated. This IEA annotation is incorrect and should be removed. Supporting Evidence: PMID:8207080 Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2, which is activated shortly before S-phase entry
GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation consistent with the IBA annotation for the same term. This is the correct molecular function for cyclin E1. Reason: Consistent with the IBA annotation. This is the defining molecular function of cyclin E1 as a CDK2 regulatory subunit.
GO:0019901 protein kinase binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for protein kinase binding. Cyclin E1 does bind CDK2 (a protein kinase), so this is technically correct but vague. Reason: Cyclin E1 binds CDK2, which is a protein kinase. UniProt states "Interacts with CDK2 protein kinase to form a serine/threonine kinase holoenzyme complex" (PMID:15660127). While more informative terms exist (GO:0016538), this IEA annotation is not incorrect and can be retained as a broader term.
GO:0097134 cyclin E1-CDK2 complex	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation consistent with IBA annotation for the same term. Reason: Consistent with the IBA annotation. Cyclin E1 is a defining component of the cyclin E1-CDK2 complex (ComplexPortal CPX-2015).
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation from HPA immunofluorescence data showing nucleoplasmic localization. Reason: Nucleoplasmic localization is consistent with cyclin E1 being a nuclear protein that functions in cell cycle regulation within the nucleus. This is supported by multiple lines of evidence.
GO:0000082 G1/S transition of mitotic cell cycle	NAS PMID:15838514 Cyclin E in normal and neoplastic cell cycles.	ACCEPT	Summary: NAS annotation from a review article on cyclin E in normal and neoplastic cell cycles. Confirms the core function of cyclin E1 in G1/S transition. Reason: Core function annotation supported by review literature. PMID:15838514 states "Cyclin E-Cdk2 has long been considered an essential and master regulator of progression through G1 phase of the cell cycle." Supporting Evidence: PMID:15838514 Cyclin E-Cdk2 has long been considered an essential and master regulator of progression through G1 phase of the cell cycle
GO:0000082 G1/S transition of mitotic cell cycle	IMP PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulatin...	ACCEPT	Summary: IMP annotation from a study showing miR-16 targets cyclin E1 to inhibit mesenchymal stem cell proliferation and induce cell cycle arrest. Cyclin E1 knockdown/downregulation caused cell cycle arrest, supporting its role in G1/S transition. Reason: The study shows that miR-16 targets cyclin E1, and over-expression of miR-16 "inhibited the proliferation and migration of decidua-derived mesenchymal stem cells and induced cell-cycle arrest by targeting cyclin E1" (PMID:23083510). This supports cyclin E1 involvement in G1/S transition. Supporting Evidence: PMID:23083510 over-expressed miR-16 inhibited the proliferation and migration of decidua-derived mesenchymal stem cells and induced cell-cycle arrest by targeting cyclin E1
GO:1902462 positive regulation of mesenchymal stem cell proliferation	IMP PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulatin...	KEEP AS NON CORE	Summary: IMP annotation from miR-16 study in pre-eclampsia. While cyclin E1 promotes proliferation of mesenchymal stem cells (shown by miR-16 targeting), this is a very specific biological context (decidual MSCs in pre-eclampsia) rather than a core function. Reason: Cyclin E1 does promote proliferation in MSCs as shown by the miR-16 study, but this is a pleiotropic effect of its general cell cycle role in a specific cell type context, not a core evolved function. The annotation is technically supported but represents a context-specific manifestation. Supporting Evidence: PMID:23083510 over-expressed miR-16 inhibited the proliferation and migration of decidua-derived mesenchymal stem cells and induced cell-cycle arrest by targeting cyclin E1
GO:0000082 G1/S transition of mitotic cell cycle	IMP PMID:25732226 MicroRNA-30c-2-3p negatively regulates NF-κB signaling and c...	ACCEPT	Summary: IMP annotation from study showing miR-30c-2-3p targets CCNE1 in breast cancer cells. Inhibition of CCNE1 phenocopied effects on cell proliferation. Reason: The study confirms that CCNE1 downregulation affects cell cycle progression. "inhibition of CCNE1 phenocopied the effects on cell proliferation" (PMID:25732226). Supports G1/S transition role. Supporting Evidence: PMID:25732226 inhibition of CCNE1 phenocopied the effects on cell proliferation
GO:0005515 protein binding	IPI PMID:21540187 Inhibitor of cyclin-dependent kinase (CDK) interacting with ...	MARK AS OVER ANNOTATED	Summary: Interaction with INCA1 (inhibitor of CDK interacting with cyclin A1). UniProt confirms "Interacts with INCA1" (PMID:21540187). Reason: Generic protein binding is uninformative. The actual interaction is between cyclin E1 and INCA1, a CDK inhibitor. UniProt confirms this interaction. Supporting Evidence: PMID:21540187 we identified INCA1 as an interaction partner and a substrate of cyclin A1 in complex with CDK2
GO:0005634 nucleus	IDA PMID:19942931 Mtd/Bok takes a swing: proapoptotic Mtd/Bok regulates tropho...	ACCEPT	Summary: Nuclear localization of cyclin E1 observed in trophoblast cells. The study shows Mtd-L colocalizes with cyclin E1 in the nuclear compartment. Reason: Nuclear localization confirmed by immunofluorescence in proliferating trophoblast cells. "Mtd expression in proliferating cells colocalized with cyclin E1, a G(1)/S phase cell cycle regulator" (PMID:19942931). Consistent with UniProt annotation. Supporting Evidence: PMID:19942931 Mtd expression in proliferating cells colocalized with cyclin E1, a G(1)/S phase cell cycle regulator
GO:0005515 protein binding	IPI PMID:17434132 Structure of a Fbw7-Skp1-cyclin E complex: multisite-phospho...	MARK AS OVER ANNOTATED	Summary: Structural study of Fbw7-Skp1-cyclin E complex. Demonstrates the molecular basis for cyclin E recognition by SCF-FBXW7 for ubiquitin-mediated degradation. This is a well-characterized interaction. Reason: Generic protein binding is uninformative. The actual finding is the structural basis for FBXW7 recognition of phosphorylated cyclin E degrons. This interaction is critical for cyclin E turnover but "protein binding" does not capture the functional significance. Supporting Evidence: PMID:17434132 Cyclin E degradation is triggered by multisite phosphorylation, which induces binding to the SCF(Fbw7) ubiquitin ligase complex
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-187520	ACCEPT	Summary: Reactome TAS annotation for nucleoplasmic localization, from the Cyclin E/A:Cdk2-mediated phosphorylation of p27/p21 reaction. Reason: Cyclin E-CDK2 mediates phosphorylation of p27/p21 in the nucleoplasm as part of the Skp2-mediated degradation pathway. Consistent with nuclear function.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-187552	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from binding of phospho-p27/p21 to SCF(Skp2):Cks1 complex. Reason: Consistent with established nucleoplasmic function of cyclin E-CDK2 complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-187574	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from degradation of ubiquitinated p27/p21 by 26S proteasome. Reason: Consistent with nucleoplasmic localization during cell cycle regulation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-187575	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from ubiquitination of phospho-p27/p21. Reason: Consistent with nucleoplasmic localization during cell cycle regulation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-188350	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from CAK-mediated phosphorylation of Cyclin E:Cdk2. Reason: Consistent with nucleoplasmic localization during cell cycle regulation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-188386	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from association of Rb with Cyclin E:Cdk2 complexes. Reason: Consistent with nucleoplasmic localization for RB1 phosphorylation by cyclin E-CDK2.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-188390	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from Cyclin E:CDK2-mediated phosphorylation of RB1. Reason: Consistent with nucleoplasmic localization for the core function of RB1 phosphorylation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-69005	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from Cdc6 phosphorylation by CDK. Reason: Consistent with nucleoplasmic localization. Cdc6 phosphorylation by cyclin E-CDK2 is part of DNA replication licensing.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-69195	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from phosphorylation of Cyclin E:CDK2 complexes by WEE1. Reason: Consistent with nucleoplasmic localization during cell cycle checkpoint regulation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-69199	ACCEPT	Summary: Reactome TAS annotation for nucleoplasm, from dephosphorylation of Cyclin E:Cdk2 complexes by Cdc25A. Reason: Consistent with nucleoplasmic localization during cell cycle regulation.
GO:0005829 cytosol	TAS Reactome:R-HSA-157906	ACCEPT	Summary: Reactome TAS annotation for cytosol, from translocation of Cyclin E:Cdk2 complex to the nucleus. Cyclin E-CDK2 is present in the cytosol before nuclear translocation. Reason: Cyclin E-CDK2 complexes form in the cytosol before translocation to the nucleus. The Reactome reaction R-HSA-157906 specifically describes this translocation, implying cytosolic presence.
GO:0005829 cytosol	TAS Reactome:R-HSA-69191	ACCEPT	Summary: Reactome TAS annotation for cytosol, from formation of Cyclin E:Cdk2 complexes. Reason: Cyclin E-CDK2 complex formation occurs in the cytosol. Consistent with known biology of cyclin-CDK complex assembly.
GO:0005829 cytosol	TAS Reactome:R-HSA-8961846	ACCEPT	Summary: Reactome TAS annotation for cytosol, from CCNE1 gene transcription stimulated by E2F1. This annotation seems to be about the gene product being present in cytosol in the context of its transcriptional regulation. Reason: While the Reactome reaction is about transcriptional regulation, cyclin E1 protein is synthesized in the cytosol. Consistent with cytoplasmic localization evidence.
GO:0005829 cytosol	TAS Reactome:R-HSA-9706390	ACCEPT	Summary: Reactome TAS annotation for cytosol from RHOBTB3 interaction at trans-Golgi network. This is a less well-characterized interaction. Reason: While the RHOBTB3 interaction context is less well characterized for cyclin E1, cytosolic presence is consistent with known nucleocytoplasmic shuttling of cyclin E.
GO:0006468 protein phosphorylation	IMP PMID:10500095 Cullin-3 targets cyclin E for ubiquitination and controls S ...	MODIFY	Summary: PMID:10500095 describes Cullin-3 targeting cyclin E for ubiquitination. The paper discusses cyclin E phosphorylation as a signal for degradation, and cyclin E-CDK2 complex kinase activity, but cyclin E itself does not catalyze phosphorylation. Cyclin E1 is a regulatory subunit, not a kinase. Reason: Cyclin E1 does not catalyze protein phosphorylation itself. It is a non-enzymatic regulatory subunit that activates CDK2. The annotation should be modified to reflect that cyclin E1 regulates protein kinase activity rather than directly performing phosphorylation. PMID:10500095 discusses "cyclin E-Cdk2 complexes" where CDK2 is the catalytic subunit. The paper actually focuses on "Cyclin E is an unstable protein that is degraded in a ubiquitin- and proteasome-dependent pathway." Proposed replacements: regulation of protein kinase activity Supporting Evidence: PMID:10500095 Cyclin E is an unstable protein that is degraded in a ubiquitin- and proteasome- dependent pathway
GO:0005634 nucleus	IDA PMID:16109376 The bromodomain protein Brd4 is a positive regulatory compon...	ACCEPT	Summary: PMID:16109376 is about the bromodomain protein Brd4 and P-TEFb, not directly about cyclin E1. Brd4 interacts with cyclinT1 and Cdk9. The reference appears questionable for a CCNE1 nuclear localization annotation, as the paper primarily concerns cyclinT1/Cdk9. However, nuclear localization of cyclin E1 is well established by multiple other lines of evidence, including UniProt annotation with PMID:7739542 and IDA from PMID:19942931. Reason: Although the specific reference PMID:16109376 may be a curatorial error (the paper focuses on Brd4/P-TEFb/cyclinT1/Cdk9 rather than cyclin E1), the nuclear localization of CCNE1 itself is unambiguously established. UniProt states "SUBCELLULAR LOCATION: Nucleus" with experimental evidence, and multiple other IDA annotations confirm nuclear localization (PMID:19942931). The annotation conclusion is correct even if the cited reference is questionable. Supporting Evidence: PMID:16109376 Proteomic analysis revealed that Brd4 interacts with cyclinT1 and Cdk9 that constitutes core positive transcription elongation factor b (P-TEFb)
GO:0005515 protein binding	IPI PMID:9891079 Cyclin E associates with BAF155 and BRG1, components of the ...	MARK AS OVER ANNOTATED	Summary: Interaction with BAF155 and BRG1, components of the SWI-SNF chromatin remodeling complex. Cyclin E associates with these components and modulates BRG1-induced growth arrest. Reason: Generic protein binding is uninformative. The actual finding is a specific interaction between cyclin E and SWI-SNF complex components (BAF155, BRG1) that may modulate chromatin remodeling during cell cycle progression. Supporting Evidence: PMID:9891079 BRG1 and BAF155, mammalian homologs of yeast SWI2 and SWI3, respectively, are found in cyclin E complexes and are phosphorylated by cyclin E-associated kinase activity
GO:0000082 G1/S transition of mitotic cell cycle	NAS PMID:8207080 Alternative splicing of human cyclin E.	ACCEPT	Summary: NAS annotation from the alternative splicing paper. The paper establishes cyclin E as a G1 cyclin that activates CDK2 for S-phase entry. Reason: PMID:8207080 confirms "Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2, which is activated shortly before S-phase entry, thus defining it as a G1 cyclin." Core function annotation. Supporting Evidence: PMID:8207080 Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2, which is activated shortly before S-phase entry, thus defining it as a G1 cyclin

Gene Description

Existing Annotations Review

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