Affinage

CDKN1C

Cyclin-dependent kinase inhibitor 1C · UniProt P49918

Length
316 aa
Mass
32.2 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKN1C (p57KIP2) is a maternally expressed, imprinted cyclin-dependent kinase inhibitor that enforces cell-cycle exit, quiescence, and differentiation across diverse stem and progenitor cell populations. It directly binds and inhibits cyclin–CDK complexes—particularly CDK1 to trigger trophoblast giant cell endoreduplication and CDK2 upon p38-mediated T143 phosphorylation during stress responses—and additionally inhibits RNA Pol II CTD kinases CDK7 and CDK9 at E2F1-regulated promoters, thereby coupling cell-cycle arrest to transcriptional reprogramming (PMID:18981479, PMID:22569127, PMID:20106982). Its protein levels are tightly controlled by proteasomal degradation mediated by the E3 ligases SCF-SKP2, SCF-FBXO22, and RNF26, with Akt phosphorylation promoting cytoplasmic relocalization and turnover, while IMAGe syndrome–causing gain-of-function mutations in the PCNA-binding domain impair this degradation and cause growth restriction (PMID:22634751, PMID:24098681, PMID:36127346, PMID:34650035, PMID:23421998). Epigenetic silencing of CDKN1C is maintained by EZH2-catalyzed H3K27me3 directed by the lncRNA Kcnq1ot1 and by Lsh-dependent DNA methylation at the imprinting control region, while chromatin remodelers such as SMARCB1 and transcription factors including E47, Hes1, and ARX dynamically regulate its expression in tissue-specific contexts (PMID:19340297, PMID:30651140, PMID:15647320, PMID:19221586, PMID:16899237).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Establishing that p57 is not merely redundant with p21 but cooperatively essential for cell-cycle exit during skeletal muscle differentiation resolved whether CIP/KIP family members have overlapping developmental roles.

    Evidence p57/p21 double-knockout mice failed to form myotubes, with persistent proliferation and apoptosis in myoblasts

    PMID:9925645

    Open questions at the time
    • Relative individual contributions of p57 versus p21 to each step of myogenesis not separated
    • Downstream CDK targets in myoblast exit not identified
  2. 2000 High

    Discovery of a CDK-inhibition-independent function—direct physical stabilization of MyoD—revealed that p57 acts as a multifunctional scaffold linking cell-cycle arrest to myogenic transcription factor activity.

    Evidence Co-IP of endogenous proteins, domain mapping, and half-life measurements showed p57 N-terminal helix binds MyoD bHLH domain and increases MyoD stability

    PMID:10764802

    Open questions at the time
    • Whether p57–MyoD interaction is required in vivo for myogenesis not shown genetically
    • Mechanism by which p57 prevents MyoD degradation (e.g., which E3 ligase is blocked) not identified
  3. 2004 High

    Genetic epistasis between p57 and PTHrP demonstrated that p57 is a critical downstream effector of growth plate signaling, placing it at the nexus of endocrine/paracrine regulation of chondrocyte proliferation.

    Evidence p57 deletion partially rescued PTHrP-null bone phenotype; PTH/PTHrP treatment reduced p57 mRNA and protein in chondrocytes

    PMID:15124025

    Open questions at the time
    • Transcription factors mediating PTHrP-dependent p57 repression not identified
    • Whether p57 inhibits CDK4/6 or CDK2 in chondrocytes not resolved
  4. 2005 High

    Identification of Lsh-dependent DNA methylation at the Cdkn1c differentially methylated region established a direct chromatin-remodeling mechanism for paternal allele silencing of this imprinted locus.

    Evidence ChIP, bisulfite sequencing, and allele-specific expression in Lsh-deficient embryos showed Lsh binds the Cdkn1c DMR and maintains CpG methylation

    PMID:15647320

    Open questions at the time
    • How Lsh is recruited specifically to the Cdkn1c DMR not determined
    • Relationship between Lsh-mediated methylation and Kcnq1ot1-mediated silencing not clarified
  5. 2006 High

    Two concurrent findings—Hes1-mediated transcriptional repression in pancreatic progenitors and timer function in oligodendrocyte precursors—established p57 as a broadly used intracellular timer converting developmental signals into cell-cycle exit decisions.

    Evidence Hes1/p57 double-KO mouse epistasis and promoter analysis; clonal OPC culture with quantitative p57 accumulation measurements

    PMID:16899237 PMID:17553990

    Open questions at the time
    • Mechanism of progressive p57 protein accumulation in OPCs not defined
    • Whether Hes1 binds the p57 promoter directly in vivo confirmed only by promoter analysis
  6. 2006 Medium

    RNAi-mediated p57 knockdown caused cortical neuron migration defects independent of differentiation, revealing a CDK-inhibitor function in post-mitotic neuronal migration not previously appreciated.

    Evidence In utero electroporation of shRNA against p57 in mouse neocortex

    PMID:17092932

    Open questions at the time
    • Direct CDK target mediating migration effect not identified
    • Single knockdown approach without genetic KO confirmation
  7. 2008 High

    Demonstrating that p57 specifically inhibits CDK1 to initiate endoreduplication in trophoblast stem cells defined the molecular selectivity of p57 for a particular CDK in a physiological context.

    Evidence CDK1-selective inhibitor phenocopied p57 in TS cells; p57 mutant TS cells failed to endoreduplicate; CDK kinase assays confirmed CDK1 targeting

    PMID:18981479

    Open questions at the time
    • How p57 selectivity for CDK1 over CDK2 is achieved structurally not resolved
    • Whether other CIP/KIP members can compensate for CDK1 inhibition in vivo
  8. 2009 High

    Identification of EZH2-mediated H3K27me3 as a direct silencing mark at the CDKN1C locus linked Polycomb repression to p57 loss in cancer, establishing a targetable epigenetic axis.

    Evidence ChIP for H3K27me3 in breast cancer cells; pharmacological EZH2 and HDAC inhibition de-repressed CDKN1C

    PMID:19340297

    Open questions at the time
    • Mechanism recruiting EZH2 specifically to CDKN1C in breast cancer cells not fully defined
    • Whether H3K27me3 removal is sufficient to restore full p57 function not tested
  9. 2010 High

    Discovering that p57 is recruited to E2F1-regulated promoters and directly inhibits CDK7/CDK9 phosphorylation of the RNA Pol II CTD expanded p57's role from a pure cell-cycle inhibitor to a transcriptional co-regulator.

    Evidence ChIP showed p57 at E2F1 target promoters; in vitro kinase assays demonstrated p57 blocks CDK7/CDK9 CTD phosphorylation; Co-IP mapped E2F1–p57 interaction domains

    PMID:20106982

    Open questions at the time
    • Genome-wide scope of p57's transcriptional regulatory role not mapped
    • Whether CDK7 vs CDK9 inhibition has distinct transcriptional consequences not distinguished
  10. 2012 High

    Human genetic and functional studies established that gain-of-function PCNA-binding-domain mutations in CDKN1C cause IMAGe syndrome by dramatically increasing protein stability, linking the PCNA-dependent degradation pathway to a Mendelian growth restriction disorder.

    Evidence Exome sequencing of IMAGe families; Co-IP showing loss of PCNA binding; Drosophila expression assay; cycloheximide chase and proteasome inhibitor experiments

    PMID:22634751 PMID:24098681

    Open questions at the time
    • Identity of the E3 ligase that ubiquitinates p57 via PCNA interaction not determined at this stage
    • Whether IMAGe mutations affect CDK-inhibitory activity in addition to stability not fully resolved
  11. 2012 High

    Identification of p38-SAPK phosphorylation at T143 as a signal that enhances p57–CDK2 binding revealed how stress signals are converted into cell-cycle delay through post-translational modification of a CKI.

    Evidence In vitro kinase assay, mutagenesis of T143, Co-IP showing enhanced CDK2 binding, genetic validation with p38/p57 inactivation

    PMID:22569127

    Open questions at the time
    • Whether T143 phosphorylation also affects p57 interactions with CDK1 or other partners not tested
    • Phosphatase responsible for reversing this modification not identified
  12. 2012 Medium

    CSN6-facilitated SKP2-mediated ubiquitination established the first defined E3 ligase pathway for proteasomal p57 turnover, with subsequent studies confirming SKP2, FBXO22, and RNF26 as parallel degradation routes.

    Evidence Co-IP and ubiquitination assays for CSN6/SKP2/p57; later confirmed by FBXO22 (2022) and RNF26 (2021) ubiquitination assays with functional cell-cycle readouts

    PMID:23187808 PMID:34650035 PMID:36127346 PMID:38102140

    Open questions at the time
    • Relative contributions of SKP2, FBXO22, and RNF26 in different tissues not compared
    • Degron motifs recognized by each E3 ligase not precisely mapped beyond PCNA-binding domain
  13. 2013 High

    Conditional knockout of p57 in adult hippocampal neural stem cells demonstrated that p57 is essential for maintaining quiescence and preventing stem cell exhaustion, generalizing p57's role as a quiescence gatekeeper beyond embryonic development.

    Evidence Conditional p57 KO in NSCs with BrdU/Ki67 tracing; initial neurogenesis burst followed by long-term NSC depletion

    PMID:23481253

    Open questions at the time
    • Whether p57 enforces quiescence through CDK inhibition alone or also through transcriptional co-regulation in NSCs not resolved
    • Upstream signals that maintain p57 expression in quiescent NSCs not fully defined
  14. 2013 Medium

    Akt-mediated phosphorylation at Ser282/Thr310 was shown to drive cytoplasmic relocalization and accelerated ubiquitin-dependent degradation of p57, revealing how growth factor signaling inactivates p57 to promote proliferation.

    Evidence Phosphorylation mapping, subcellular fractionation, ubiquitination assays in HER2-overexpressing cells

    PMID:23421998

    Open questions at the time
    • Whether Akt phosphorylation feeds into SKP2 or a distinct E3 ligase pathway not determined
    • In vivo relevance of Akt–p57 axis not validated genetically
  15. 2017 High

    DNA fiber assays revealed that p57 slows replication fork speed in erythroid progenitors and that its downregulation triggers a global fork speed increase coinciding with differentiation, establishing an unexpected S-phase-intrinsic role for a CKI in cell-fate decisions.

    Evidence DNA fiber assay in sorted erythroid progenitors from p57 KO and WT mice, flow cytometry for S-phase length

    PMID:28560351

    Open questions at the time
    • Molecular mechanism by which p57 slows replication forks (direct fork association vs. CDK inhibition at forks) not resolved
    • Whether fork speed regulation is specific to erythroid cells or general
  16. 2018 High

    Dynamic cytoplasmic-to-nuclear translocation of p57 in muscle stem cells demonstrated that subcellular localization is a regulated switch controlling the timing of growth arrest and differentiation onset.

    Evidence Immunofluorescence and subcellular fractionation in primary myoblasts; Cdkn1c KO showed differentiation defects

    PMID:30284969

    Open questions at the time
    • Kinase or signal controlling nuclear import timing not identified
    • Whether cytoplasmic p57 has active non-CDK functions in myoblasts not explored
  17. 2019 Medium

    The lncRNA Kcnq1ot1 was shown to recruit EZH2 to deposit H3K27me3 at an intragenic MyoD-binding region of p57, directly linking imprinting-associated lncRNA to the epigenetic silencing mechanism and its reversal during myogenic differentiation.

    Evidence ChIP, RNA immunoprecipitation, and chromatin oligo-affinity precipitation with allele-specific analysis in myoblasts

    PMID:30651140

    Open questions at the time
    • Whether Kcnq1ot1 uses the same EZH2-recruitment mechanism in non-muscle tissues not tested
    • Structural basis for Kcnq1ot1–EZH2 interaction not characterized
  18. 2022 High

    Identification of p57 as a molecular gatekeeper of the reserve stem cell state in gastric chief cells extended its quiescence-maintenance role to adult tissue homeostasis and injury response, showing that rapid p57 loss is required for damage-induced regeneration.

    Evidence scRNA-seq, lineage tracing, in vivo constitutive p57 expression, and corpus organoid experiments

    PMID:35523142

    Open questions at the time
    • Upstream signal that triggers rapid p57 downregulation upon gastric injury not identified
    • Whether p57 loss alone is sufficient for chief cell dedifferentiation or requires cooperating signals

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: which E3 ligase mediates PCNA-dependent p57 degradation in the IMAGe syndrome context; how p57 mechanistically slows replication forks; what signals control the cytoplasmic-to-nuclear translocation switch; and whether p57's transcriptional co-regulatory function via CDK7/CDK9 inhibition is genome-wide or restricted to specific promoter classes.
  • PCNA-dependent E3 ligase identity unresolved
  • Structural basis for p57 at replication forks unknown
  • Nuclear import signal and its regulatory kinase/phosphatase not mapped
  • Genome-wide ChIP for p57 occupancy at promoters not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 10 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 11 R-HSA-1266738 Developmental Biology 9 R-HSA-392499 Metabolism of proteins 6 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-4839726 Chromatin organization 5
Partners
CDK1CDK2CDK7E2F1EZH2FBXO22MYOD1SKP2

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 p57(KIP2) and p21(CIP1) redundantly control skeletal muscle differentiation at the myogenin step; mice lacking both fail to form myotubes, displaying increased myoblast proliferation and apoptosis, and endoreplication in residual myotubes, indicating cell-cycle exit is required for myogenin function and muscle-specific gene expression. Double-knockout mouse genetics, histology, BrdU incorporation, gene expression analysis Genes & development High 9925645
2008 p57/KIP2 triggers endoreduplication and differentiation of trophoblast stem cells into trophoblast giant cells by inhibiting CDK1 activity; p57 is required specifically for CDK1 inhibition to initiate endoreduplication, while p21 concurrently suppresses CHK1 to prevent apoptosis. CDK1 inhibitor (RO3306) treatment, p57/p21 mutant TS cell analysis, CDK kinase assays, immunofluorescence Genes & development High 18981479
2000 p57(Kip2) physically interacts with MyoD via its N-terminal alpha-helix domain (located between the CDK and cyclin binding sites) and the basic HLH domain of MyoD, stabilizing MyoD by increasing its half-life independently of CDK inhibitory activity. Co-immunoprecipitation of overexpressed and endogenous proteins, transactivation assays, site-directed mutagenesis, protein half-life measurement The Journal of biological chemistry High 10764802
2012 Gain-of-function missense mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome; IMAGe-associated mutations result in loss of PCNA binding; expression of mutant CDKN1C in Drosophila caused severe eye growth defects compared to wild-type, suggesting a gain-of-function mechanism. Exome sequencing, Sanger sequencing, identity-by-descent analysis, Drosophila targeted expression assay, Co-IP for PCNA binding Nature genetics High 22634751
2013 IMAGe-associated mutations in the PCNA-binding domain of CDKN1C dramatically increase protein stability via impaired proteasomal degradation, representing a gain-of-function mechanism; wild-type CDKN1C is normally degraded via the proteasome pathway. Cycloheximide chase, proteasome inhibitor (MG132) treatment, Western blot, Co-IP for PCNA binding PloS one High 24098681
2015 IMAGe-associated mutations in the PCNA-binding domain of CDKN1C increase protein stability and prevent cell cycle progression into S phase; mutant CDKN1C inhibits cell proliferation more strongly than wild-type or BWS-mutant CDKN1C. Flow cytometry, cell proliferation assays, protein stability measurements, overexpression of wild-type and mutant CDKN1C Cell division Medium 25861374
2012 p57(Kip2) is phosphorylated at T143 by the p38 stress-activated protein kinase (SAPK), which enhances p57 association with and inhibition of Cdk2, resulting in cell-cycle delay and cell survival upon osmotic stress, oxidative stress, and ionomycin treatment. In vitro kinase assay, co-IP, genetic inactivation of p38 and p57, cell viability assays, stress-response assays The EMBO journal High 22569127
2009 CDKN1C is a direct epigenetic target of the histone methyltransferase EZH2; EZH2-mediated H3K27me3 at the CDKN1C locus represses its expression in breast cancer cells, and this can be reversed by EZH2 inhibition synergized with HDAC inhibitors. ChIP for H3K27me3, EZH2 inhibition, HDAC inhibitor treatment, quantitative RT-PCR, Western blot PloS one High 19340297
2010 CDKN1C negatively regulates RNA polymerase II CTD phosphorylation in an E2F1-dependent manner; CDKN1C is recruited to E2F1-regulated promoters, interacts with CDK7 and CDK9, and blocks their ability to phosphorylate the RNA Pol II CTD in vitro; E2F1 and CDKN1C form stable complexes mediated by two E2F1 domains. ChIP, co-IP, GST pull-down in vitro kinase assay, RNAi, adenoviral overexpression, Western blot for phospho-CTD The Journal of biological chemistry High 20106982
2004 PTHrP's proliferative actions in chondrocytes are mediated at least in part through suppression of p57 expression; genetic ablation of p57 partially rescues the PTHrP-null bone phenotype, and PTHrP/PTH decreases p57 mRNA and protein levels in chondrocytes. Double-knockout mouse genetics (p57/PTHrP-null), metatarsal organ culture, PTH treatment, immunohistochemistry, in situ hybridization The Journal of clinical investigation High 15124025
2006 p57 is a direct transcriptional target repressed by Notch effector Hes1; inactivation of Hes1 upregulates p57 in pancreatic progenitors leading to cell cycle arrest and precocious differentiation; p57/Hes1 double-null embryos show expansion of progenitor populations due to absence of apoptosis. Genetic double-knockout mouse, immunohistochemistry, in situ hybridization, BrdU labeling, promoter analysis Developmental biology High 16899237
2013 p57 is required for neural stem cell (NSC) quiescence in the adult hippocampus; p57 deletion initially increases neurogenesis but leads to NSC exhaustion and impaired neurogenesis in aged mice; reduction of p57 in NSCs contributes to abrogation of quiescence by extrinsic neurogenic stimuli such as running. Conditional p57 knockout in NSCs, BrdU/Ki67 labeling, behavioral stimulation (running), immunofluorescence The EMBO journal High 23481253
2006 p57(Kip2) levels increase over time in proliferating oligodendrocyte precursor cells (OPCs) and regulate how many times an OPC can divide before differentiating, functioning as an intracellular timer; all daughters of an OPC clone express similar p57 levels. In vitro clonal analysis, immunostaining, overexpression and knockdown in OPCs The Journal of neuroscience Medium 17553990
2006 p57 and p27 are required for neuronal migration in the developing mouse neocortex; knockdown of p57 by RNAi causes significant delay in cortical plate migration without affecting neuronal differentiation. In utero electroporation, RNAi knockdown, immunohistochemistry, cortical plate analysis The Journal of biological chemistry Medium 17092932
2018 Subcellular localization of p57(Kip2) is dynamic in muscle stem cells; p57 is initially cytoplasmic in activated/proliferating myoblasts and undergoes progressive nuclear translocation to cause growth arrest during differentiation; Cdkn1c-deficient myoblasts show differentiation defects and increased proliferation. Mouse molecular genetics (Cdkn1c KO), immunofluorescence, subcellular fractionation, primary myoblast isolation and culture eLife High 30284969
2017 p57KIP2 mediates an S phase-dependent cell fate switch in early erythroid progenitors; p57KIP2-mediated slowing of replication forks is required for progenitor self-renewal, and down-regulation of p57KIP2 at differentiation onset causes a global increase in replication fork speed and shorter S phase. In vivo erythroid progenitor analysis, DNA fiber assay, flow cytometry, p57KIP2 KO mouse Science advances High 28560351
2013 ARX directly represses Cdkn1c transcription; loss of Arx in cortical progenitors causes CDKN1C overexpression and reduced IPC proliferation; ARX was identified as a direct transcriptional regulator of CDKN1C by transcriptional profiling and direct binding studies. Conditional KO mouse, transcriptional profiling, ChIP, in situ hybridization, immunohistochemistry Cerebral cortex Medium 23968833
2019 The lncRNA Kcnq1ot1 promotes H3K27me3 accumulation at an intragenic MyoD-binding region of p57Kip2, suppressing its maternal allele expression during muscle differentiation; upon differentiation, MyoD binding to this region coincides with loss of EZH2/H3K27me3 and p57 de-repression. ChIP, RNA immunoprecipitation, Chromatin Oligo-affinity Precipitation, siRNA knockdown, allele-specific expression analysis Epigenetics & chromatin Medium 30651140
2012 CSN6 (COP9 signalosome subunit 6) associates with p57(Kip2) and Skp2 (an SCF E3 ligase component), facilitating Skp2-mediated ubiquitination and proteasomal degradation of p57; CSN6 overexpression destabilizes p57 and promotes cell cycle progression. Co-IP, ubiquitination assay, CSN6 overexpression/knockdown, Western blot, cell proliferation assays Cell cycle Medium 23187808
2013 Akt phosphorylates p57(Kip2) at Ser282 or Thr310, causes cytoplasmic localization, accelerates protein turnover via ubiquitination, and thereby promotes HER2-mediated cell proliferation and tumorigenicity. Co-IP, phosphorylation mapping, ubiquitination assay, subcellular fractionation, cell proliferation/transformation assays Cell cycle Medium 23421998
2022 FBXO22, a component of the SCF E3 ubiquitin ligase complex, physically interacts with p57Kip2 and mediates its ubiquitination and proteasomal degradation, promoting G1/S phase progression and cervical cancer cell proliferation. Co-IP, ubiquitination assay, protein half-life measurement, overexpression/knockdown, xenograft Cell death & disease Medium 36127346
2021 RNF26 degrades p57(CDKN1C) to regulate cell cycle progression in bladder cancer; RNF26 expression is transcriptionally promoted by FOXM1 via the MuvB complex, forming a FOXM1/RNF26/p57 axis that modulates cell cycle and bladder cancer progression. Co-IP, Western blot, cell cycle analysis, gain- and loss-of-function experiments, ChIP Cell death & disease Medium 34650035
2005 Lsh, a SNF2 chromatin remodeling protein, directly associates with the 5' differentially methylated region (DMR) at the Cdkn1c promoter and controls CpG methylation at this locus to maintain paternal allele silencing; loss of Lsh causes reactivation of the silent paternal Cdkn1c allele. Chromatin immunoprecipitation (ChIP), allele-specific expression analysis, bisulfite sequencing, Lsh-deficient embryos Development High 15647320
2018 Targeted demethylation of the imprinting control region 2 (ICR2) using an ICR2-TET1 fusion protein represses p57 expression and promotes proliferation of human islet β cells while maintaining glucose-sensing functionality. TALE-TET1 epigenetic editing, Ki-67 staining, p57 Western blot, human islet transplantation in diabetic mice The Journal of clinical investigation Medium 30352048
2022 p57Kip2 is a molecular gatekeeper of the reserve stem cell state of gastric chief cells; p57 is constitutively expressed in homeostatic chief cells, rapidly diminishes after injury to allow robust proliferation, and its overexpression impairs injury response and locks cells in a reserve stem cell state. scRNA-seq, doxycycline-induced lineage tracing, in vivo constitutive p57 expression, corpus organoids, p57 overexpression Cell stem cell High 35523142
2019 p57KIP2 expression is strongly induced by increased cell density in normal trophoblast stem cells and mediates contact inhibition; loss of p57KIP2 expression in androgenetic (CHM-derived) trophoblast stem cells causes resistance to contact inhibition and enhanced proliferation at confluence. Knockout and overexpression studies in human trophoblast stem cells, cell density assays Proceedings of the National Academy of Sciences of the United States of America Medium 31792181
2011 p57 downregulation in hepatocellular carcinoma cells increases CDK4/cyclin D1 and CDK2/cyclin E complex activities and accelerates invasion via controlling LIMK1 activity; stable p57 knockdown increases xenograft growth. Stable shRNA knockdown, CDK kinase immunocomplex assays, invasion assay, LIMK1 activity measurement, xenograft Carcinogenesis Medium 22002319
2019 In Drosophila, the cyclin-dependent kinase inhibitor Dacapo (ortholog of p57KIP2) determines whether neural stem cells enter G0 or G2 quiescence; the dorsal patterning factor Msh binds directly to the Dap locus and induces Dap expression in dorsal NSCs, resulting in G0 arrest. ChIP, Drosophila genetics (msh and dap mutants), immunostaining, cell cycle staging Developmental cell Medium 30905769
2017 The bHLH transcription factor E47 directly activates Cdkn1c expression by binding to a distal enhancer at the CDKN1C gene locus; E47 overexpression upregulates p57(KIP2) and disturbs layer-specific neurogenesis in vivo. ChIP-Seq, RNA-Seq, in utero electroporation, ChIP validation Development Medium 28939666
2002 p73β, but not p53, activates transcription of CDKN1C (p57KIP2) and KvLQT1; p73 can regulate imprinted genes through mechanisms not shared by p53. Transient transfection reporter assays, Northern blot, comparison of p53 and p73 activity Proceedings of the National Academy of Sciences of the United States of America Medium 11891335
2023 SKP2 E3-ubiquitin ligase directly targets p57Kip2 for degradation in fusion-negative rhabdomyosarcoma, preventing myogenic differentiation; MYOD drives SKP2 overexpression via binding to an intronic enhancer, forming a MYOD-SKP2-p57 axis. Co-IP, ubiquitination assay, ChIP, RNA-seq, SKP2 knockdown/overexpression, in vivo xenograft Nature communications High 38102140
2009 SMARCB1 restoration transcriptionally activates CDKN1C in rhabdoid tumor cells through increased histone H3 and H4 acetylation at the CDKN1C promoter; CDKN1C expression induces cell cycle arrest and knockdown of CDKN1C increases proliferation. Inducible SMARCB1 expression, ChIP for histone acetylation, siRNA knockdown, flow cytometry PloS one Medium 19221586
2019 EZH2-mediated H3K27me3 at the CDKN1C promoter region is promoted by CDYL, which recruits EZH2 to silences CDKN1C transcription; EZH2 inhibition by GSK126 de-represses CDKN1C and decreases CDYL-induced chemoresistance in SCLC cells. ChIP-qPCR, Co-IP, GST pull-down, EMSA, bisulfite sequencing, gain- and loss-of-function experiments Theranostics Medium 31367252
2015 Paternal allelic mutation at Kcnq1 reduces pancreatic β-cell mass by disrupting Kcnq1ot1 expression, which leads to increased Cdkn1c expression on the normally silenced maternal allele through altered histone modification at the Cdkn1c promoter in pancreatic islets. Kcnq1 KO mouse (allele-specific), ChIP for histone modifications, β-cell mass measurement, islet gene expression Proceedings of the National Academy of Sciences of the United States of America Medium 26100882

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step. Genes & development 348 9925645
2010 Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors. Cell cycle (Georgetown, Tex.) 190 20519948
2013 Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA. American journal of cancer research 154 24224124
2008 Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. Genes & development 153 18981479
2009 CDKN1C (p57) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cells. PloS one 142 19340297
1999 Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. Journal of medical genetics 138 10424811
2012 Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nature genetics 131 22634751
2006 p57 and Hes1 coordinate cell cycle exit with self-renewal of pancreatic progenitors. Developmental biology 130 16899237
1999 Oppositely imprinted genes p57(Kip2) and igf2 interact in a mouse model for Beckwith-Wiedemann syndrome. Genes & development 130 10601037
2001 Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS. Human molecular genetics 125 11181570
2000 p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. Molecular human reproduction 124 11044465
2003 Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith-Wiedemann syndrome. Journal of medical genetics 123 14627666
2013 p57 controls adult neural stem cell quiescence and modulates the pace of lifelong neurogenesis. The EMBO journal 120 23481253
2005 ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome. Nucleic acids research 103 15888726
2011 The hallmarks of CDKN1C (p57, KIP2) in cancer. Biochimica et biophysica acta 91 21447370
2000 Stabilization of MyoD by direct binding to p57(Kip2). The Journal of biological chemistry 89 10764802
2005 Genomic imprinting of IGF2, p57(KIP2) and PEG1/MEST in a marsupial, the tammar wallaby. Mechanisms of development 85 15652708
2002 Induction of p57(KIP2) expression by p73beta. Proceedings of the National Academy of Sciences of the United States of America 85 11891335
2002 Immunohistochemical characterization of p57(KIP2) expression in early hydatidiform moles. Human pathology 79 12514787
2001 Podocyte expression of the CDK-inhibitor p57 during development and disease. Kidney international 79 11737597
2011 MicroRNA-221 inhibits CDKN1C/p57 expression in human colorectal carcinoma. Acta pharmacologica Sinica 78 21278784
2006 The cyclin-dependent kinase inhibitors p57 and p27 regulate neuronal migration in the developing mouse neocortex. The Journal of biological chemistry 78 17092932
2014 CDKN1C mutations: two sides of the same coin. Trends in molecular medicine 77 25262539
2011 Fetal overgrowth in the Cdkn1c mouse model of Beckwith-Wiedemann syndrome. Disease models & mechanisms 77 21729874
2011 p57(Kip2) and cancer: time for a critical appraisal. Molecular cancer research : MCR 76 21816904
2018 LncRNA SNHG17 promotes gastric cancer progression by epigenetically silencing of p15 and p57. Journal of cellular physiology 75 30256413
2009 Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells. European journal of human genetics : EJHG 73 19513094
1987 Amino acid sequence of P-57, a neurospecific calmodulin-binding protein. Biochemistry 70 2962637
1986 Physicochemical and hydrodynamic characterization of P-57, a neurospecific calmodulin binding protein. Biochemistry 67 2948561
2007 A crucial role for p57(Kip2) in the intracellular timer that controls oligodendrocyte differentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 17553990
2004 The cyclin-dependent kinase inhibitor p57(Kip2) mediates proliferative actions of PTHrP in chondrocytes. The Journal of clinical investigation 65 15124025
2001 Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors. European journal of endocrinology 65 11454518
2010 CDKN1C (p57(Kip2)) analysis in Beckwith-Wiedemann syndrome (BWS) patients: Genotype-phenotype correlations, novel mutations, and polymorphisms. American journal of medical genetics. Part A 61 20503313
2015 Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization. Human mutation 60 26077438
2005 Lsh controls silencing of the imprinted Cdkn1c gene. Development (Cambridge, England) 60 15647320
2002 Domain regulation of imprinting cluster in Kip2/Lit1 subdomain on mouse chromosome 7F4/F5: large-scale DNA methylation analysis reveals that DMR-Lit1 is a putative imprinting control region. Genome research 60 12466290
2004 Methylation at mouse Cdkn1c is acquired during postimplantation development and functions to maintain imprinted expression. Genomics 59 15533713
2018 Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases. International journal of molecular sciences 54 29614816
2013 ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c. Cerebral cortex (New York, N.Y. : 1991) 54 23968833
2020 Functional Versatility of the CDK Inhibitor p57Kip2. Frontiers in cell and developmental biology 53 33117811
2015 Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β-cell mass by epigenetic modification of Cdkn1c. Proceedings of the National Academy of Sciences of the United States of America 53 26100882
2005 Multiple mechanisms downregulate CDKN1C in human bladder cancer. International journal of cancer 53 15551363
2018 Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication. The Journal of clinical investigation 51 30352048
2008 CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer. BMC cancer 51 18325103
2017 Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch. Science advances 50 28560351
2012 The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress. The EMBO journal 49 22569127
2009 Imprinted CDKN1C is a tumor suppressor in rhabdoid tumor and activated by restoration of SMARCB1 and histone deacetylase inhibitors. PloS one 49 19221586
2000 Decreased expression of p57(KIP2)mRNA in human bladder cancer. British journal of cancer 49 10944603
2014 A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. The Journal of clinical endocrinology and metabolism 47 25057881
2006 Imprinting disruption of the CDKN1C/KCNQ1OT1 domain: the molecular mechanisms causing Beckwith-Wiedemann syndrome and cancer. Cytogenetic and genome research 46 16575194
2001 Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations. Genomics 46 11414765
2010 p57: A multifunctional protein in cancer (Review). International journal of oncology 45 20428755
2006 Multiplex short tandem repeat DNA analysis confirms the accuracy of p57(KIP2) immunostaining in the diagnosis of complete hydatidiform mole. Human pathology 45 16949913
2022 p57Kip2 imposes the reserve stem cell state of gastric chief cells. Cell stem cell 43 35523142
2018 Cellular localization of the cell cycle inhibitor Cdkn1c controls growth arrest of adult skeletal muscle stem cells. eLife 42 30284969
2017 Visualizing Changes in Cdkn1c Expression Links Early-Life Adversity to Imprint Mis-regulation in Adults. Cell reports 40 28147266
2014 Relevance of genomic imprinting in intrauterine human growth expression of CDKN1C, H19, IGF2, KCNQ1 and PHLDA2 imprinted genes. Journal of assisted reproduction and genetics 39 24986528
2001 Dynamic temporal and spatial regulation of the cdk inhibitor p57(kip2) during embryo morphogenesis. Mechanisms of development 39 11677056
2019 CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter. Theranostics 38 31367252
2008 Determination of KCNQ1OT1 and H19 methylation levels in BWS and SRS patients using methylation-sensitive high-resolution melting analysis. European journal of human genetics : EJHG 38 18854861
2020 Long non-coding RNA GAS5 accelerates oxidative stress in melanoma cells by rescuing EZH2-mediated CDKN1C downregulation. Cancer cell international 36 32308561
2015 miR-25 promotes glioma cell proliferation by targeting CDKN1C. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 25960208
2013 CDK inhibitor p57 (Kip2) is downregulated by Akt during HER2-mediated tumorigenicity. Cell cycle (Georgetown, Tex.) 36 23421998
2009 CDKN1C mutations in HELLP/preeclamptic mothers of Beckwith-Wiedemann Syndrome (BWS) patients. Placenta 36 19386358
2020 LncRNA-BLACAT1 Facilitates Proliferation, Migration and Aerobic Glycolysis of Pancreatic Cancer Cells by Repressing CDKN1C via EZH2-Induced H3K27me3. Frontiers in oncology 35 33072570
2002 A pro-apoptotic effect of the CDK inhibitor p57(Kip2) on staurosporine-induced apoptosis in HeLa cells. Biochemical and biophysical research communications 35 12176039
2013 Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome. PloS one 33 24098681
2011 Downregulation of p57 accelerates the growth and invasion of hepatocellular carcinoma. Carcinogenesis 33 22002319
2021 The FOXM1/RNF26/p57 axis regulates the cell cycle to promote the aggressiveness of bladder cancer. Cell death & disease 32 34650035
2019 Loss of p57KIP2 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells. Proceedings of the National Academy of Sciences of the United States of America 32 31792181
2015 Inhibition of MiR-199a-5p reduced cell proliferation in autosomal dominant polycystic kidney disease through targeting CDKN1C. Medical science monitor : international medical journal of experimental and clinical research 32 25588980
2020 Imprinted Cdkn1c genomic locus cell-autonomously promotes cell survival in cerebral cortex development. Nature communications 31 31924768
2017 The E2A splice variant E47 regulates the differentiation of projection neurons via p57(KIP2) during cortical development. Development (Cambridge, England) 31 28939666
2012 CDK inhibitor p57 (Kip2) is negatively regulated by COP9 signalosome subunit 6. Cell cycle (Georgetown, Tex.) 30 23187808
2022 Fbxo22 promotes cervical cancer progression via targeting p57Kip2 for ubiquitination and degradation. Cell death & disease 28 36127346
2012 The multiple roles of the cyclin-dependent kinase inhibitory protein p57(KIP2) in cerebral cortical neurogenesis. Developmental neurobiology 27 22076965
2000 A potential role for p15(Ink4b) and p57(Kip2) in liver development. FEBS letters 27 11042273
2018 TBX3 promotes proliferation of papillary thyroid carcinoma cells through facilitating PRC2-mediated p57KIP2 repression. Oncogene 26 29511350
2005 The Ankrd2, Cdkn1c and calcyclin genes are under the control of MyoD during myogenic differentiation. Journal of molecular biology 26 15890200
2019 The long non-coding RNA Kcnq1ot1 controls maternal p57 expression in muscle cells by promoting H3K27me3 accumulation to an intragenic MyoD-binding region. Epigenetics & chromatin 25 30651140
2019 Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57KIP2/Dacapo. Developmental cell 24 30905769
2016 Epigenetic Characterization of CDKN1C in Placenta Samples from Non-syndromic Intrauterine Growth Restriction. Frontiers in genetics 24 27200075
1995 A constitutional BWS-related t(11;16) chromosome translocation occurring in the same region of chromosome 16 implicated in Wilms' tumors. Genes, chromosomes & cancer 23 7534105
2015 Cellular Response upon Stress: p57 Contribution to the Final Outcome. Mediators of inflammation 22 26491224
2012 The role of AHI1 and CDKN1C in cutaneous T-cell lymphoma progression. Experimental dermatology 22 23171462
2004 Searching for genomic variants in IGF2 and CDKN1C in Silver-Russell syndrome patients. Molecular genetics and metabolism 22 15234339
2000 Possible involvement of the p57(Kip2) gene in bone metabolism. Biochemical and biophysical research communications 22 10708569
2016 CDKIs p18(INK4c) and p57(Kip2) are involved in quiescence of CML leukemic stem cells after treatment with TKI. Cell cycle (Georgetown, Tex.) 21 26985855
2006 EGCG-targeted p57/KIP2 reduces tumorigenicity of oral carcinoma cells: role of c-Jun N-terminal kinase. Toxicology and applied pharmacology 21 17196232
2002 Increased expression of vascular endothelial growth factor in placentas of p57(Kip2) null embryos. FEBS letters 21 12482580
1999 A human p57(KIP2) transgene is not activated by passage through the maternal mouse germline. Human molecular genetics 21 10545601
2020 lncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer. Molecular therapy. Nucleic acids 20 32679543
2011 The usefulness of p57(KIP2) immunohistochemical staining and genotyping test in the diagnosis of the hydatidiform mole. Pathology, research and practice 20 21767919
2010 CDKN1C negatively regulates RNA polymerase II C-terminal domain phosphorylation in an E2F1-dependent manner. The Journal of biological chemistry 20 20106982
2021 CDKN1C-mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib. Cancer science 19 33792119
2017 Dopaminergic and behavioural changes in a loss-of-imprinting model of Cdkn1c. Genes, brain, and behavior 19 28857482
2015 Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase. Cell division 19 25861374
2000 Analysis of CDKN1C in Beckwith Wiedemann syndrome. Human mutation 19 10862080
2023 MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting. Nature communications 18 38102140
2019 Analysis of CDKN1C in fetal growth restriction and pregnancy loss. F1000Research 18 31497289