CDKN1C encodes p57Kip2, an intrinsically disordered CIP/Kip-family inhibitor of cyclin-dependent kinases. Its N-terminal inhibitory region restrains cyclin-CDK activity and cell-cycle progression. Predominantly nuclear p57 coordinates proliferation with differentiation and development, with additional context-dependent effects on transcription and protein interactions. CDKN1C is an imprinted locus expressed predominantly from the maternal allele. Loss-of-function variants can cause Beckwith-Wiedemann syndrome, whereas IMAGe-associated variants in its PCNA-binding region increase growth suppression. Mouse studies establish roles in lens, skeletal, renal, placental and other organ development, with tissue-dependent compensation by p27.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045930 negative regulation of mitotic cell cycle | IBA GO_REF:0000033 | ACCEPT | Summary: p57 restrains progression through the mitotic cell cycle. Reason: The conserved CKI activity and direct p57 inhibition and G1-arrest experiments support this core process. The PAINT assertion is a phylogenetic inheritance judgment; its extant evidence list is not a measure of confidence. The historical node placement was not reconstructed here. Supporting Evidence: PMID:7729684 Overexpression of p57KIP2 arrests cells in G1. file:human/CDKN1C/CDKN1C-source-evidence.json |
| GO:0050680 negative regulation of epithelial cell proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: p57 limits epithelial proliferation in a defined cellular setting. Reason: Human limbal epithelial-cell p57 depletion restores proliferation after TGF-beta treatment. This supports the inherited process as a tissue-context application of CKI function. The human product in the PAINT evidence list is legitimate descendant evidence, not circular support. |
| GO:0004860 protein kinase inhibitor activity | IEA GO_REF:0000043 | MODIFY | Summary: The broad kinase-inhibitor label can represent the established CDK-inhibitor function more precisely. Reason: The keyword mapping is biologically compatible with p57, but CDK inhibition is directly supported by functional protein and cellular experiments. Refine this assertion to the specific inhibitor activity; this is not a claim that p57 cannot influence other kinases. Proposed replacements: cyclin-dependent protein serine/threonine kinase inhibitor activity |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | IEA GO_REF:0000002 | ACCEPT | Summary: CDK inhibition is the defining molecular activity. Reason: The InterPro inference is corroborated by functional inhibition of cyclin A-CDK2 by full-length p57 and its N-terminal domain, and by p57-dependent inhibition of CDK2 outputs in cells. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: The nucleus is a principal site of p57 action. Reason: Independent human-cell immunolocalization places endogenous p57 predominantly in nuclei. Nuclear NPAT phosphorylation and histone-gene regulation provide functional context beyond a targeting-sequence prediction. The source GOA uses located_in, not an independent assertion of activity in every nuclear subcompartment. |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000117 | MODIFY | Summary: The demonstrated transcriptional repression concerns RNA polymerase II. Reason: Refine the broad ARBA process to RNAPII transcriptional repression. Human p57 depletion increases histone H4 output in HeLa cells, and human WI38 reporter experiments show inhibition. Separate RNAPII-CTD experiments combine endogenous human-cell evidence with mouse-p57 overexpression, rather than establishing direct DNA recognition by p57. Proposed replacements: negative regulation of transcription by RNA polymerase II |
| GO:0051726 regulation of cell cycle | IEA GO_REF:0000002 | MODIFY | Summary: The cell-cycle regulation has a supported inhibitory direction. Reason: The InterPro inference is correct but broad. Direct p57 CKI and G1-arrest evidence supports negative regulation of the mitotic cell cycle, already represented by the independent IBA. This source-specific refinement introduces no additional annotation. Proposed replacements: negative regulation of mitotic cell cycle |
| GO:0005515 protein binding | IPI PMID:16289477 The cell cycle regulator p27Kip1 interacts with MCM7, a DNA ... | UNDECIDED | Summary: The exact p57-MCM7 experiment remains unresolved. Reason: The original IPI partner is MCM7/P33993. The accessible abstract foregrounds p27; it cannot establish whether p57 was also tested. The full publisher article was inaccessible, and the bounded IntAct query recovered no corresponding record. Neither fact demonstrates a wrong-protein attribution or a negative interaction. Preserve this source assertion pending its actual target assay. |
| GO:0005515 protein binding | IPI PMID:18660753 A new ubiquitin ligase involved in p57KIP2 proteolysis regul... | KEEP AS NON CORE | Summary: Endogenous p57 associates with FBXL12 in human cells. Reason: PMID:18660753 Figure 2A/B reports reciprocal endogenous HeLa co-immunoprecipitation. This directly supports the original FBXL12 association despite the separate mouse-p57 T329A construct experiments. Retain generic association under the campaign policy; being an ubiquitination substrate does not assign the ligase activity to p57. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: The BioPlex screen supports a CDK4-p57 association. Reason: The exact positive IntAct record EBI-54980069 contains human CDK4 bait with a C-terminal tandem tag and p57 prey in HCT116 cells. Retain the screen association under campaign policy. This affinity-purification record does not itself measure inhibition or establish a purified binary interface. Supporting Evidence: file:human/CDKN1C/CDKN1C-source-evidence.json intact:EBI-54980069|imex:IM-29278-27393 |
| GO:0005515 protein binding | IPI PMID:9106657 New functional activities for the p21 family of CDK inhibito... | KEEP AS NON CORE | Summary: p57 is associated with CDK4 in the cited family study. Reason: The exact positive record EBI-519276 supports anti-bait co-immunoprecipitation in human U2OS cells. The abstract includes p57 among proteins promoting cyclin D-CDK4 assembly, but quantitative assembly, low-dose activation and endogenous mammary-cell findings differ among family members. Keep this association without transferring p21-specific functional results to p57. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 can repress RNAPII-dependent transcription in selected contexts. Reason: The mouse donor traces to Nurr1 reporter inhibition in PMID:14671317; that work also separates neuronal maturation from CKI-dependent arrest. Independent human NPAT/histone studies and endogenous CTD-phosphorylation evidence support transcriptional regulation. Retain the contextual process without treating p57 as a sequence-specific DNA-binding factor. Supporting Evidence: file:human/CDKN1C/CDKN1C-source-evidence.json |
| GO:0001501 skeletal system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 contributes to skeletal development. Reason: The mouse donor paper measures skeletal malformations and delayed ossification after p57 loss, with substantial rescue by p27 expressed from the p57 locus and reduced excess BrdU labeling in bone. Retain this developmental application of CKI activity with its ortholog scope. |
| GO:0001822 kidney development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 is required for normal renal development in the mouse donor. Reason: The donor study directly examines renal-papilla dysplasia. It persists after p27 knock-in, with altered interstitial expression, so the experiment does not isolate a universal CDK-independent mechanism. Retain the developmental inference without claiming a direct human renal assay. |
| GO:0001890 placenta development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 supports placental development and trophoblast organization. Reason: Mouse loss-of-function studies show abnormal placental structure; PMID:21729874 directly examines the maternal-fetal interface and trophoblast populations. The phenotype is a developmental consequence of p57 function and varies with strain and intrauterine competition. Retain it outside the representative molecular core. |
| GO:0007096 regulation of exit from mitosis | IEA GO_REF:0000107 | MODIFY | Summary: The donor establishes restraint of cycling during differentiation. Reason: PMID:9784491 Figures 3 and 4 and the BrdU Methods demonstrate continued S-phase entry in p57-deficient mouse lens and placenta, amplified by p27 loss. This supports cycling restraint, not the anaphase/telophase-to-G1 transition specified by GO:0007096. Refine the electronic transfer to negative regulation of mitotic cell cycle; the previous G1/S-transition replacement described entry into S phase rather than its inhibition. Proposed replacements: negative regulation of mitotic cell cycle |
| GO:0030099 myeloid cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 participates in a myeloid maturation context. Reason: The mouse donor paper tests p57 adenoviral rescue of MBT-1-deficient common myeloid progenitors and observes improved maturation by CD34/Fc-receptor profiles after culture. Human TF-1 expression kinetics are corroborating context, not the rescue experiment. Retain this developmental inference. |
| GO:0030325 adrenal gland development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 contributes to adrenal development. Reason: The mouse donor study examines adrenal enlargement after p57 loss and its amelioration by p27 knock-in. Human IMAGe genetics independently links altered CDKN1C function with adrenal hypoplasia. These are dosage-sensitive developmental consequences, not an adrenal-specific molecular activity. |
| GO:0035264 multicellular organism growth | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 dosage regulates organismal growth. Reason: Mouse knockout and knock-in studies directly assess growth; the direction varies with developmental stage and placental function. Human IMAGe variants increase growth suppression, whereas BWS loss of function causes overgrowth. Retain the broad growth process without imposing a single direction across contexts. Supporting Evidence: file:human/CDKN1C/CDKN1C-source-evidence.json |
| GO:0042551 neuron maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 contributes to late neuronal maturation in the donor system. Reason: The mouse study finds altered midbrain dopamine markers and survival late in gestation; MN9D experiments distinguish Nurr1-cooperative maturation from CDK-dependent arrest. Retain the ortholog-supported developmental role without inferring that all neuronal maturation requires the same mechanism. |
| GO:0043010 camera-type eye development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 contributes to eye development through lens differentiation. Reason: The mouse donor study directly examines lens defects and their substantial rescue by p27 knock-in, with excess BrdU labeling corrected in the lens. This supports the inherited developmental term without turning it into the representative biochemical function. |
| GO:0055123 digestive system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 contributes to digestive-system development in the mouse donor. Reason: Intestinal defects after p57 loss are examined histologically and improved by p27 knock-in; E2F1 loss also ameliorates the phenotype. The source supports a developmental consequence of cell-cycle/apoptosis regulation, not a digestive enzymatic function. |
| GO:0060065 uterus development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 contributes to uterine development in the donor model. Reason: The mouse study compares uterine morphology and muscle-layer thickness after p57 loss and p27 knock-in. Retain the organ-development inference with that species and genotype scope. |
| GO:0060669 embryonic placenta morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 contributes to embryonic placental morphogenesis. Reason: The donor paper examines placental dysplasia and necrosis after p57 loss, persisting in p27-knock-in animals with altered trophoblast protein expression. This supports the existing developmental inference; it does not establish imprinting activity of p57 protein. |
| GO:0071514 genomic imprinting | IEA GO_REF:0000107 | REMOVE | Summary: The donor supports regulation of an imprinted locus, not imprint establishment by p57 protein. Reason: PMID:19276117 Figure 1D and the knock-in Results and Methods test parent-of-origin expression after replacing the mouse p57 coding region with HA-p27. Maternal-only expression persists at that locus. This documents an imprinted gene being regulated, not p57 establishing or propagating epigenetic imprints as required by GO:0071514. Remove this source-specific gene-product transfer while retaining imprinted CDKN1C expression as biological context. |
| GO:1902746 regulation of lens fiber cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: p57 helps coordinate lens-fiber differentiation with withdrawal from cycling. Reason: The donor study compares p57/p27 mutant mouse lenses, BrdU labeling and crystallin expression. It directly supports the contextual differentiation process. The same experiments do not resolve a phase-specific mitotic-exit activity. |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | IMP PMID:11746698 Intrinsic structural disorder and sequence features of the c... | ACCEPT | Summary: The functional p57 protein inhibits cyclin A-CDK2. Reason: The authentic abstract explicitly reports active full-length p57 and a functionally independent N-terminal cyclin A-CDK2-inhibitory domain. Full assay details were not recovered, but the stated activity agrees with independent p57 kinase-output experiments; preserve the original IMP attribution. Supporting Evidence: PMID:11746698 functionally independent as a cyclin A-CDK2 inhibitor |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | IDA PMID:19170105 CDK inhibitors selectively diminish cell cycle controlled ac... | ACCEPT | Summary: p57 inhibits CDK2 activity and its NPAT phosphorylation output. Reason: PMID:19170105 Figure 5A measures CDK2 activity using histone H1; Figures 3/4 separately measure NPAT phospho-epitopes in cells. Both human and mouse p57 suppress NPAT phosphorylation, while cyclin-binding-defective constructs fail. These distinguish genuine CKI activity from the proposed additional substrate-complex mechanism. Supporting Evidence: PMID:19170105 p57(KIP2) in inhibiting the CDK2 dependent phosphorylation of p220(NPAT) |
| GO:0005515 protein binding | IPI PMID:28425505 Novel interactions of the von Hippel-Lindau (pVHL) tumor sup... | KEEP AS NON CORE | Summary: Human p57 physically associates with pVHL. Reason: The paper tests sequence-defined human CDKN1C cDNA in yeast two-hybrid and human HEK293T co-immunoprecipitation experiments. Retain the observed association; this does not assign VHL ubiquitin-ligase activity or demonstrate that p57 is a VHL substrate. |
| GO:0140678 molecular function inhibitor activity | IMP PMID:11746698 Intrinsic structural disorder and sequence features of the c... | MODIFY | Summary: The measured molecular inhibition is cyclin-dependent kinase inhibition. Reason: The source PMID:11746698 concerns functional inhibition of cyclin A-CDK2 by p57. Replace the broad molecular-function-inhibitor label with the measured activity, already independently represented. The older E2F1 mechanism was not established by this particular citation. Proposed replacements: cyclin-dependent protein serine/threonine kinase inhibitor activity Supporting Evidence: |
| GO:0044877 protein-containing complex binding | IPI PMID:11746698 Intrinsic structural disorder and sequence features of the c... | ACCEPT | Summary: p57 binds the cyclin A2-CDK2 complex as part of its core CDK-inhibitor role. Reason: The original IPI assertion identifies ComplexPortal:CPX-2006, the human CCNA2-CDK2 complex, in its source record. Retain this specific complex-binding fact alongside the separately annotated inhibitor activity. PMID:11746698 reports inhibitory activity for p57 and its N-terminal domain; the available abstract corroborates that functional context, while the detailed original binding Methods remain uninspected. There is no contrary evidence warranting replacement of the curated binding assertion. The complex interaction is central to p57 function, and inhibitor activity is already represented by independent and same-paper annotations. Supporting Evidence: file:human/CDKN1C/CDKN1C-source-evidence.json ComplexPortal:CPX-2006 |
| GO:0005515 protein binding | IPI PMID:22634751 Mutations in the PCNA-binding domain of CDKN1C cause IMAGe s... | KEEP AS NON CORE | Summary: Wild-type human p57 associates with PCNA. Reason: In PMID:22634751, endogenous PCNA co-immunoprecipitates with FLAG-tagged wild-type human CDKN1C from HEK293T cells, whereas the tested IMAGe alleles disrupt that association. Retain the physical association; neither the mutation phenotype nor this co-IP alone assigns a DNA-replication catalytic role to p57. |
| GO:0005515 protein binding | IPI PMID:19170105 CDK inhibitors selectively diminish cell cycle controlled ac... | KEEP AS NON CORE | Summary: p57 occurs in an NPAT-containing complex. Reason: PMID:19170105 Figure 6 supports co-immunoprecipitation and dependence on p57 cyclin-binding competence. The paper explicitly leaves open whether cyclin-CDK proteins bridge the association. Retain source-scoped protein binding without replacing it with an unproved direct NPAT-inhibitor activity. |
| GO:0005634 nucleus | IDA PMID:16943770 Targeted inhibition of p57 and p15 blocks transforming growt... | ACCEPT | Summary: Endogenous p57 is predominantly nuclear in human limbal cells. Reason: The direct immunofluorescence experiment reports principally nuclear staining with a weaker cytoplasmic pool. This agrees with the nuclear setting of independently demonstrated p57 function. Preserve this localization annotation without asserting compartment-restricted expression. |
| GO:0005737 cytoplasm | IDA PMID:16943770 Targeted inhibition of p57 and p15 blocks transforming growt... | KEEP AS NON CORE | Summary: A cytoplasmic p57 pool is directly observed. Reason: The same human limbal-cell staining and fractionation study detects cytoplasmic p57 as well as the predominant nuclear pool. Retain this broader localization; the assay does not independently identify a cytoplasmic molecular function. Supporting Evidence: |
| GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway | IMP PMID:16943770 Targeted inhibition of p57 and p15 blocks transforming growt... | MARK AS OVER ANNOTATED | Summary: The source establishes a downstream antiproliferative response to TGF-beta. Reason: The full Methods and Results measure TGF-beta-induced p57 expression and restoration of BrdU incorporation/MTT signal after p57 depletion. They support p57 as an effector of growth suppression, but do not distinguish that role from an increase in TGF-beta receptor pathway signaling, as required by GO:0030511. Mark the regulatory specificity as over-annotated while retaining the demonstrated epithelial-proliferation role; this is not evidence that feedback is impossible. Supporting Evidence: |
| GO:0050680 negative regulation of epithelial cell proliferation | IMP PMID:16943770 Targeted inhibition of p57 and p15 blocks transforming growt... | KEEP AS NON CORE | Summary: p57 mediates a TGF-beta-dependent reduction of epithelial proliferation. Reason: The human primary limbal-cell assay directly tests p57 siRNA and restores BrdU incorporation after TGF-beta treatment. Retain this correct tissue-context manifestation of the core inhibitor activity rather than equating it with activation of the upstream receptor pathway. Supporting Evidence: |
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Download this section (compressed HTML)Q: Does the original PMID:16289477 MCM7 study directly test p57/CDKN1C, and what construct and assay underlie the human IPI annotation?
Q: Which p57 developmental functions in humans require CDK inhibition, and which depend on distinct interaction surfaces or cell-specific protein stability?
Q: Does p57 enhance TGF-beta receptor signaling independently of its established downstream antiproliferative effect in limbal epithelial cells?
Q: Should the mouse P49919 IMP annotation to genomic imprinting from PMID:19276117 be reviewed upstream to distinguish preserved parent-of-origin expression at the Cdkn1c locus from an imprint-establishing activity of p57 protein?
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