CDKN1C encodes p57Kip2, a cyclin-dependent kinase inhibitor of the CIP/Kip family that functions as a tumor suppressor by binding to and inhibiting cyclin/CDK complexes, particularly cyclin E/CDK2, cyclin A/CDK2, and cyclin D/CDK4. The N-terminal kinase inhibitory domain (KID) blocks ATP binding to CDKs through molecular mimicry. The protein contains a unique PAPA (proline-alanine repeat) domain, a QT box mediating additional protein interactions, bipartite nuclear localization signals (NLS), and a C-terminal PCNA-binding domain. p57Kip2 dynamically shuttles between cytoplasm (during proliferation) and nucleus (during differentiation) to regulate cell cycle exit. The gene is imprinted and expressed exclusively from the maternal allele; loss-of-function mutations cause Beckwith-Wiedemann syndrome and IMAGe syndrome. Beyond CDK inhibition, p57Kip2 inhibits JNK/SAPK signaling independently and regulates E2F1-mediated transcription by inhibiting RNA polymerase II CTD phosphorylation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045930 negative regulation of mitotic cell cycle | IBA GO_REF:0000033 | ACCEPT | Summary: Negative regulation of mitotic cell cycle - p57Kip2 inhibits CDK complexes to arrest cells in G1 phase. Reason: Core function. p57Kip2 inhibits cyclin/CDK complexes, preventing G1/S transition and negatively regulating mitotic cell cycle. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md The fundamental biological consequence of p57Kip2-mediated CDK inhibition is arrest of the cell cycle in the G1 phase file:human/CDKN1C/CDKN1C-deep-research-falcon.md See deep research file for comprehensive analysis |
| GO:0050680 negative regulation of epithelial cell proliferation | IBA GO_REF:0000033 | ACCEPT | Summary: Negative regulation of epithelial cell proliferation - p57Kip2 inhibits proliferation in multiple cell types including epithelial cells. Reason: Correct. p57Kip2 inhibits proliferation across multiple cell types including epithelial cells through CDK inhibition. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 inhibits the kinase activity of multiple cyclin/CDK complexes |
| GO:0004860 protein kinase inhibitor activity | IEA GO_REF:0000043 | MODIFY | Summary: Protein kinase inhibitor activity - p57Kip2 inhibits CDKs which are protein kinases. Reason: Correct but should be more specific. p57Kip2 specifically inhibits cyclin-dependent protein kinases, not kinases generally. Proposed replacements: cyclin-dependent protein serine/threonine kinase inhibitor activity Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 is that of a tight-binding, strong inhibitor of cyclin/cyclin-dependent kinase complexes |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | IEA GO_REF:0000002 | ACCEPT | Summary: CDK inhibitor activity - core molecular function of p57Kip2. Reason: Core molecular function. The N-terminal KID domain binds to and inhibits cyclin E/CDK2, cyclin A/CDK2, and cyclin D/CDK4 complexes. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 inhibits the kinase activity of multiple cyclin/CDK complexes in vitro, including cyclin E/CDK2, cyclin A/CDK2, and cyclin D1,2/CDK4 complexes |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization - p57Kip2 localizes to nucleus during differentiation. Reason: Core localization. p57Kip2 contains bipartite NLS and translocates to nucleus during differentiation where it inhibits CDKs. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md As differentiation proceeds and myoblasts express progressively higher levels of MYOGENIN (a late myogenic marker), p57Kip2 demonstrates increasingly strong nuclear localization |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000117 | ACCEPT | Summary: Negative regulation of transcription - p57Kip2 inhibits E2F1-mediated transcription through RNA pol II CTD inhibition. Reason: Correct. p57Kip2 binds E2F1 and inhibits RNA polymerase II CTD phosphorylation by blocking CDK7 and CDK9. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md CDKN1C-E2F1 complex negatively regulates transcription by inhibiting phosphorylation of the RNA polymerase II C-terminal domain |
| GO:0051726 regulation of cell cycle | IEA GO_REF:0000002 | ACCEPT | Summary: Regulation of cell cycle - core function as CDK inhibitor. Reason: Core function. p57Kip2 regulates cell cycle by inhibiting G1 cyclin/CDK complexes. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md CDKN1C encoding the p57Kip2 protein, is a critical cell cycle regulator |
| GO:0005515 protein binding | IPI PMID:16289477 The cell cycle regulator p27Kip1 interacts with MCM7, a DNA ... | REMOVE | Summary: Protein binding from interactome study. Reason: Generic "protein binding" is uninformative per curation guidelines. The specific interaction (with MCM7) should be captured by more specific terms. Supporting Evidence: PMID:16289477 we report a novel function for the cyclin-dependent kinase inhibitor p27Kip1 in inhibiting DNA replication through its interaction with MCM7 [study focused on p27, not p57] |
| GO:0005515 protein binding | IPI PMID:18660753 A new ubiquitin ligase involved in p57KIP2 proteolysis regul... | REMOVE | Summary: Protein binding from ubiquitin ligase study. Reason: Generic "protein binding" is uninformative. Study examined FBL12-mediated degradation of p57. Supporting Evidence: PMID:18660753 FBL12 formed an SCF(FBL12) complex and directly ubiquitinated p57(KIP2) in a phosphorylation-dependent manner |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Protein binding from high-throughput interactome study. Reason: Generic "protein binding" from large-scale study is uninformative per curation guidelines. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks |
| GO:0005515 protein binding | IPI PMID:9106657 New functional activities for the p21 family of CDK inhibito... | REMOVE | Summary: Protein binding from functional study of CDK inhibitors. Reason: Generic "protein binding" is uninformative. The specific CDK interactions are captured by GO:0004861. Supporting Evidence: PMID:9106657 the CDK inhibitors p21(CIP), p27(KIP), and p57(KIP2) all promote the association of cdk4 with the D-type cyclins |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Negative regulation of transcription by RNA pol II - p57Kip2 inhibits E2F1-mediated transcription. Reason: Correct. p57Kip2 binds E2F1 and inhibits CDK7/CDK9-mediated phosphorylation of RNA pol II CTD. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 expression leads to dramatic reduction in phosphorylation of both Ser-2 and Ser-5 of the RNA polymerase II CTD |
| GO:0001501 skeletal system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Skeletal system development - p57Kip2 expressed during skeletal development. Reason: Pleiotropic developmental effect. p57Kip2 is expressed in developing cartilage and skeleton but this reflects cell cycle regulation during differentiation rather than a skeleton-specific function. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md The protein is present in all three embryonic germ layers (endoderm, mesoderm, and ectoderm) and is found in the majority of developing organs including cartilage, skeletal muscle |
| GO:0001822 kidney development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kidney development - p57Kip2 expressed during kidney development. Reason: Pleiotropic developmental effect. p57Kip2 expression in kidney reflects general role in cell cycle exit during differentiation. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md The protein is present... in the majority of developing organs including... kidney |
| GO:0001890 placenta development | IEA GO_REF:0000107 | ACCEPT | Summary: Placenta development - p57Kip2 has specialized roles in placental trophoblast. Reason: Important function. p57Kip2 regulates trophoblast endoreduplication, invasion, and placental cell layer expansion. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 plays multiple specialized roles related to trophoblast function and placental development |
| GO:0007096 regulation of exit from mitosis | IEA GO_REF:0000107 | MODIFY | Summary: Regulation of exit from mitosis. Reason: Imprecise term. p57Kip2 primarily regulates G1/S transition, not mitotic exit. The core function is preventing entry into S phase. Proposed replacements: G1/S transition of mitotic cell cycle Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md arrest of the cell cycle in the G1 phase, preventing progression from G1 into S phase |
| GO:0030099 myeloid cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Myeloid cell differentiation - p57Kip2 regulates hematopoietic stem cell quiescence. Reason: Pleiotropic effect. p57Kip2 maintains HSC quiescence but this reflects general cell cycle control rather than myeloid-specific differentiation. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 plays critical roles in maintaining quiescence and regulating function of adult stem cell populations, particularly hematopoietic stem cells |
| GO:0030325 adrenal gland development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Adrenal gland development - p57Kip2 expressed during adrenal development. Reason: Pleiotropic developmental effect. Related to IMAGe syndrome phenotype (adrenal hypoplasia) but reflects general cell cycle role. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md found in the majority of developing organs including... adrenals |
| GO:0035264 multicellular organism growth | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Multicellular organism growth - p57Kip2 loss causes overgrowth disorders. Reason: Pleiotropic effect related to BWS overgrowth phenotype. Reflects general cell cycle control across tissues. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md Beckwith-Wiedemann syndrome (BWS) represents the most clinically significant disease associated with CDKN1C mutations, being characterized as an imprinting disorder that associates... visceromegaly (enlarged internal organs) |
| GO:0042551 neuron maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuron maturation - p57Kip2 regulates neural stem cell quiescence. Reason: Pleiotropic effect. p57Kip2 maintains NSC quiescence and regulates neurogenesis through cell cycle control. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md In NSCs, p57Kip2 is abundantly expressed and its expression decreases when these cells become committed and proliferative |
| GO:0043010 camera-type eye development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Eye development - p57Kip2 expressed in developing lens. Reason: Pleiotropic developmental effect. p57Kip2 persists in lens and regulates lens fiber cell differentiation but reflects general cell cycle role. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 expression strongly decreases in most tissues but persists selectively in specific locations including... lens |
| GO:0055123 digestive system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Digestive system development - p57Kip2 expressed in developing intestine. Reason: Pleiotropic developmental effect. p57Kip2 persists in intestine but reflects general cell cycle role during differentiation. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 expression strongly decreases in most tissues but persists selectively in specific locations including... intestine |
| GO:0060065 uterus development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Uterus development - inferred from orthologs. Reason: Pleiotropic developmental effect from ortholog data. Reflects general cell cycle control during organogenesis. |
| GO:0060669 embryonic placenta morphogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Embryonic placenta morphogenesis - p57Kip2 regulates trophoblast function. Reason: Important specialized function. p57Kip2 regulates trophoblast endoreduplication and placental development. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 is involved in endoreduplication (DNA replication without mitotic cell division) that is essential for trophoblast giant cell formation |
| GO:0071514 genomic imprinting | IEA GO_REF:0000107 | ACCEPT | Summary: Genomic imprinting - CDKN1C is itself an imprinted gene. Reason: Correct. CDKN1C is an imprinted gene expressed exclusively from the maternal allele, controlled by KvDMR1 imprinting control region. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md CDKN1C occupies a unique genomic position as an imprinted gene subject to parent-of-origin-dependent expression |
| GO:1902746 regulation of lens fiber cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of lens fiber cell differentiation - p57Kip2 regulates lens development. Reason: Pleiotropic developmental effect. p57Kip2 promotes lens fiber differentiation through cell cycle exit but is not lens-specific. Supporting Evidence: file:human/CDKN1C/CDKN1C-deep-research-perplexity.md p57Kip2 expression strongly decreases in most tissues but persists selectively in specific locations including... lens |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | IMP PMID:11746698 Intrinsic structural disorder and sequence features of the c... | ACCEPT | Summary: CDK inhibitor activity demonstrated by mutational phenotype. Reason: Core function with experimental evidence. Study characterized structural disorder and CDK inhibitory function. Supporting Evidence: PMID:11746698 The cell cycle inhibitor p57Kip2 induces cell cycle arrest by inhibiting the activity of cyclin-dependent kinases. p57, although active as a cyclin A-CDK2 inhibitor, is largely unfolded or intrinsically disordered |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | IDA PMID:19170105 CDK inhibitors selectively diminish cell cycle controlled ac... | ACCEPT | Summary: CDK inhibitor activity with direct assay evidence. Reason: Core function with direct experimental evidence demonstrating CDK inhibition. Supporting Evidence: PMID:19170105 The three CDK inhibitors (CKIs) p21(CIP1/WAF1), p27(KIP1), and p57(KIP2) attenuate CDK2 activity |
| GO:0005515 protein binding | IPI PMID:28425505 Novel interactions of the von Hippel-Lindau (pVHL) tumor sup... | REMOVE | Summary: Protein binding from pVHL interaction study. Reason: Generic "protein binding" is uninformative. The specific interaction with VHL is not well characterized for functional annotation. Supporting Evidence: PMID:28425505 all three CDKN1 proteins were able to interact with pVHL30, as demonstrated by their presence in the immunoprecipitate |
| GO:0140678 molecular function inhibitor activity | IMP PMID:11746698 Intrinsic structural disorder and sequence features of the c... | ACCEPT | Summary: Molecular function inhibitor activity - parent term for CDK inhibitor activity. Reason: Correct general term. p57Kip2 inhibits CDK molecular functions. Supporting Evidence: PMID:11746698 The cell cycle inhibitor p57Kip2 induces cell cycle arrest by inhibiting the activity of cyclin-dependent kinases |
| GO:0044877 protein-containing complex binding | IPI PMID:11746698 Intrinsic structural disorder and sequence features of the c... | ACCEPT | Summary: Protein complex binding - p57Kip2 binds cyclin/CDK complexes. Reason: Correct. p57Kip2 binds to cyclin/CDK complexes to inhibit their activity. Supporting Evidence: PMID:11746698 p57, although active as a cyclin A-CDK2 inhibitor, is largely unfolded or intrinsically disordered file:human/CDKN1C/CDKN1C-deep-research-perplexity.md The binding of p57Kip2 to cyclin/CDK complexes results in formation of inactive trimeric complexes |
| GO:0005515 protein binding | IPI PMID:22634751 Mutations in the PCNA-binding domain of CDKN1C cause IMAGe s... | REMOVE | Summary: Protein binding from IMAGe syndrome mutation study. Reason: Generic "protein binding" is uninformative. The PCNA-binding domain function is better captured by specific terms. Supporting Evidence: PMID:22634751 All IMAGE-associated mutations clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding |
| GO:0005515 protein binding | IPI PMID:19170105 CDK inhibitors selectively diminish cell cycle controlled ac... | REMOVE | Summary: Protein binding from CDK inhibitor study. Reason: Generic "protein binding" is uninformative. CDK interactions captured by GO:0004861. Supporting Evidence: PMID:19170105 p57 KIP2 is more potent than p27 KIP1 or p21 CIP1/WAF1 in blocking thein situ phosphorylation of p220 NPAT at Cajal Body-related subnuclear foci |
| GO:0005634 nucleus | IDA PMID:16943770 Targeted inhibition of p57 and p15 blocks transforming growt... | ACCEPT | Summary: Nuclear localization with direct assay evidence. Reason: Core localization demonstrated experimentally. p57Kip2 translocates to nucleus during differentiation. Supporting Evidence: PMID:16943770 Cip/Kip protein p57 locates in the nucleus, and slightly expresses in the cytoplasm of human cultured limbal epithelial cells |
| GO:0005737 cytoplasm | IDA PMID:16943770 Targeted inhibition of p57 and p15 blocks transforming growt... | ACCEPT | Summary: Cytoplasmic localization with direct assay evidence. Reason: Correct. p57Kip2 localizes to cytoplasm during proliferation and shuttles to nucleus during differentiation. Supporting Evidence: PMID:16943770 Western blot and immunofluorescent staining showed that levels of p57 and p15 proteins were equally reduced in the cytoplasm and nucleus file:human/CDKN1C/CDKN1C-deep-research-perplexity.md During muscle satellite cell (MuSC) activation and early proliferation phases, p57Kip2 is predominantly restricted to the cytoplasm |
| GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway | IMP PMID:16943770 Targeted inhibition of p57 and p15 blocks transforming growt... | KEEP AS NON CORE | Summary: Positive regulation of TGF-beta signaling - p57Kip2 mediates TGF-beta-induced growth arrest. Reason: Related to TGF-beta pathway but p57Kip2 is downstream effector of TGF-beta signaling rather than a direct pathway regulator. Supporting Evidence: PMID:16943770 silencing of p57 and p15 is associated with marked phenotypic changes in the nucleus and cytoplasm in response to TGF-Ξ²s, indicating that p57 and p15 are critical downstream mediators of TGF-Ξ²s in primary cultured human limbal epithelial cells file:human/CDKN1C/CDKN1C-deep-research-perplexity.md TGFb/Smad signaling pathway stimulates p57Kip2 expression |
| GO:0050680 negative regulation of epithelial cell proliferation | IMP PMID:16943770 Targeted inhibition of p57 and p15 blocks transforming growt... | ACCEPT | Summary: Negative regulation of epithelial cell proliferation from limbal epithelial study. Reason: Correct. Study demonstrated p57Kip2 inhibits proliferation of limbal epithelial cells. Supporting Evidence: PMID:16943770 These findings demonstrate that TGF-Ξ²1 and/or TGF-Ξ²2 inhibit proliferation of primary cultured human limbal epithelial cells and that p57 and p15 play roles in this process |
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