Affinage

CDKN1C

Cyclin-dependent kinase inhibitor 1C · UniProt P49918

Length
316 aa
Mass
32.2 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKN1C/p57KIP2 is a maternally expressed, imprinted cyclin-dependent kinase inhibitor that restrains cell proliferation and controls embryonic and tissue growth in a strictly dosage-sensitive manner (PMID:17517131). Its expression is set by a layered epigenetic architecture: imprinted silencing of the paternal allele depends on a 5' differentially methylated region whose CpG methylation is acquired after implantation under control of the distal KvDMR1/ICR2 and enforced by the chromatin remodeler Lsh (PMID:15533713, PMID:15647320), while regulation also occurs over long distances through enhancers and CTCF-anchored chromatin loops tens to hundreds of kilobases from the gene (PMID:11468278, PMID:27200075); loss of maternal KvDMR1 methylation collapses CDKN1C expression in cis without altering the promoter itself (PMID:14627666). Beyond imprinting, CDKN1C transcription is gated by Polycomb EZH2/H3K27me3 — recruited via partners such as CDYL — and by SMARCB1-dependent promoter histone acetylation, and is repressed by transcription factors including ARX and the Notch effector Hes1, the latter coupling CDKN1C induction to cellular senescence (PMID:19340297, PMID:29632530, PMID:31367252, PMID:33792119, PMID:19221586, PMID:23968833, PMID:22705236). Mechanistically, CDKN1C is recruited to E2F1-regulated promoters where it binds E2F1, CDK7 and CDK9 and suppresses RNA polymerase II CTD phosphorylation at Ser-2 and Ser-5, directly linking it to transcriptional control of the cell cycle (PMID:20106982). Its activity is tuned post-transcriptionally by proteasomal turnover gated through a PCNA-binding domain and by 3'UTR-targeting miRNAs (miR-221, miR-25, miR-222) (PMID:24098681, PMID:25861374, PMID:18521080, PMID:21278784, PMID:25960208, PMID:31142732). Mutations in the PCNA-binding domain that abolish PCNA binding stabilize the protein and produce a gain-of-function growth-restriction phenotype causing IMAGe syndrome, distinct from loss-of-function overgrowth, with a related stabilizing mutation underlying a familial Russell-Silver phenotype (PMID:22634751, PMID:24098681, PMID:25861374, PMID:24065356). CDKN1C also carries growth-restricting and, separately, cell-autonomous growth-promoting/survival roles in defined lineages: it enforces myoblast differentiation through dynamic cytoplasmic-to-nuclear translocation and a MyoD feedback loop, drives terminal differentiation of neural stem cells downstream of IGF2, supports radial glial progenitor survival, and is required for brown adipose development via post-transcriptional accumulation of PRDM16 (PMID:30284969, PMID:21147088, PMID:36633189, PMID:31924768, PMID:26963625).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2004 High

    Established that monoallelic CDKN1C expression depends on a post-implantation-acquired 5' DMR methylation mark rather than a gamete-inherited one, redefining how the imprint is maintained.

    Evidence Bisulfite sequencing across gametes and embryos plus KvDMR1-deletion mouse analysis

    PMID:15533713

    Open questions at the time
    • Does not identify the enzymes that acquire the paternal methylation
    • Mechanism by which KvDMR1 directs the distal mark unresolved
  2. 2005 High

    Identified the chromatin remodeler Lsh as a direct effector that establishes 5'DMR CpG methylation to silence the paternal allele, providing a molecular actor for the imprint.

    Evidence ChIP, allele-specific expression and bisulfite sequencing in Lsh-deficient mice

    PMID:15647320

    Open questions at the time
    • How Lsh is targeted specifically to the paternal 5'DMR unknown
    • Relationship to KvDMR1 control not fully defined
  3. 2003 High

    Showed that loss of maternal KvDMR1 methylation in BWS patients reduces CDKN1C expression by >85% from ~180 kb away without promoter hypermethylation, linking a distal imprinting defect to disease through long-range cis regulation.

    Evidence qPCR, RNase protection and methylation-sensitive Southern in patient fibroblasts

    PMID:14627666

    Open questions at the time
    • Physical mechanism connecting KvDMR1 to CDKN1C silencing not shown
    • Cell-type specificity beyond fibroblasts not addressed
  4. 2007 High

    Demonstrated that CDKN1C is the dominant dosage-sensitive growth regulator of its imprinted domain, with bidirectional effects on embryo size linked to Igf1.

    Evidence BAC transgenic copy-number series and reciprocal loss-of-function in mice

    PMID:17517131

    Open questions at the time
    • Direct molecular link between CDKN1C and Igf1 not defined
    • Tissue origin of growth effect not localized
  5. 2010 High

    Revealed a transcriptional mechanism beyond classical CDK inhibition: CDKN1C is recruited to E2F1 promoters and suppresses Pol II CTD phosphorylation by inhibiting CDK7 and CDK9.

    Evidence In vivo/in vitro co-IP, ChIP, siRNA, and in vitro GST-CTD kinase assays

    PMID:20106982

    Open questions at the time
    • Genome-wide scope of E2F1-directed recruitment unknown
    • Physiological contexts where this dominates over cyclin/CDK inhibition unclear
  6. 2012 High

    Defined the molecular basis of IMAGe syndrome as gain-of-function PCNA-binding-domain mutations distinct from BWS loss-of-function, establishing a domain-specific genotype-phenotype split.

    Evidence IBD mapping, exon sequencing, and Drosophila transgenic overexpression

    PMID:22634751

    Open questions at the time
    • Cellular mechanism of gain-of-function not yet explained in this study
    • Role of PCNA binding in normal regulation undefined here
  7. 2013 High

    Explained the IMAGe gain-of-function as impaired proteasomal degradation via loss of PCNA binding, identifying protein stability as a key regulatory node.

    Evidence Cycloheximide chase, MG132 rescue and PCNA co-IP; replicated independently

    PMID:24098681 PMID:25861374

    Open questions at the time
    • E3 ligase mediating PCNA-dependent turnover not identified
    • Whether PCNA binding directly couples to degradation machinery unresolved
  8. 2013 Medium

    Distinguished a related familial Russell-Silver-causing PCNA-domain mutation that stabilizes protein without altering the cell cycle, refining the allelic-series model.

    Evidence Cell-cycle flow cytometry, cycloheximide stability assay and Sanger sequencing

    PMID:24065356

    Open questions at the time
    • Single lab; mechanism distinguishing RSS from IMAGe phenotypically not fully resolved
    • How stability without cell-cycle change produces growth restriction unclear
  9. 2009 High

    Placed CDKN1C under Polycomb control, showing EZH2/H3K27me3 directly silences it and is reversible by combined EZH2 and HDAC inhibition.

    Evidence ChIP for H3K27me3 with EZH2 knockdown/inhibition; replicated across cancers

    PMID:19340297 PMID:29632530 PMID:31367252 PMID:33792119

    Open questions at the time
    • Recruitment specificity of EZH2 to the locus not addressed here
    • Interaction with imprinting machinery unclear
  10. 2019 High

    Identified CDYL as a recruiter of EZH2 to the CDKN1C promoter, supplying a targeting mechanism for Polycomb silencing linked to chemoresistance.

    Evidence ChIP-qPCR, co-IP, GST pull-down, EMSA and in vivo tumor models

    PMID:31367252

    Open questions at the time
    • Generality of CDYL-dependent recruitment beyond SCLC unknown
    • Signals controlling CDYL engagement undefined
  11. 2012 High

    Connected SMARCB1/SWI-SNF to CDKN1C activation through promoter histone acetylation, establishing a tumor-suppressor axis in rhabdoid tumors.

    Evidence Inducible SMARCB1, siRNA rescue, acetylation ChIP and cell-cycle analysis

    PMID:19221586

    Open questions at the time
    • Direct vs indirect SMARCB1 action at the promoter not fully separated
    • Interplay with Polycomb silencing not tested
  12. 2013 High

    Showed ARX directly represses CDKN1C in cortical progenitors, tying its dosage to intermediate progenitor proliferation and neuronal output.

    Evidence Cortex-specific Arx cKO, expression profiling and ChIP at the promoter

    PMID:23968833

    Open questions at the time
    • Whether repression is direct transcriptional or context-dependent not fully resolved
    • Cofactors of ARX at the locus unknown
  13. 2008 High

    Established post-transcriptional control of CDKN1C by miR-221 acting on its 3'UTR, linking miRNA dysregulation to proliferative phenotypes.

    Evidence miR/antimiR transfection, 3'UTR luciferase reporter, Western and flow cytometry; replicated

    PMID:18521080 PMID:21278784

    Open questions at the time
    • Relative contribution versus transcriptional control in vivo unclear
    • Tissue-specific miRNA regulation not mapped
  14. 2018 High

    Demonstrated dynamic cytoplasmic-to-nuclear translocation of CDKN1C as the switch enforcing myoblast growth arrest and differentiation.

    Evidence Conditional KO, live imaging, subcellular fractionation and primary myoblast assays

    PMID:30284969

    Open questions at the time
    • Signals driving the localization switch not identified
    • Cytoplasmic function molecular targets undefined
  15. 2010 High

    Positioned Cdkn1c in a Hedgehog-Myod positive-feedback loop driving terminal muscle differentiation independent of cell-cycle exit.

    Evidence Zebrafish genetic epistasis, morpholino knockdown and in situ analysis

    PMID:21147088

    Open questions at the time
    • Molecular basis of cell-cycle-independent differentiation role unresolved
    • Conservation of the loop in mammals not tested here
  16. 2016 High

    Identified a lineage-specific role in which Cdkn1c is required for brown adipose development through post-transcriptional accumulation of PRDM16.

    Evidence Reciprocal gain/loss-of-function mice, BAT histology and co-localization imaging

    PMID:26963625

    Open questions at the time
    • Mechanism by which CDKN1C stabilizes PRDM16 not defined
    • Whether nuclear co-localization is required mechanistically unclear
  17. 2020 High

    Resolved a cell-autonomous, non-imprinted growth-promoting/survival function of Cdkn1c in radial glial progenitors, opposite to its non-cell-autonomous inhibitory role.

    Evidence MADM single-cell-resolution clonal genetic analysis

    PMID:31924768

    Open questions at the time
    • Molecular pathway of the pro-survival function unknown
    • How a CDK inhibitor promotes growth mechanistically unexplained
  18. 2023 High

    Placed Cdkn1c downstream of IGF2 as a partial mediator of neural stem cell terminal differentiation, separating its differentiation role from cell-cycle control.

    Evidence Conditional Cdkn1c KO with recombinant IGF2 infusion and lineage epistasis

    PMID:36633189

    Open questions at the time
    • Other IGF2 effectors not identified
    • Direct molecular link between IGF2 signaling and Cdkn1c induction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDKN1C's opposing cell-autonomous growth-promoting and non-cell-autonomous growth-inhibitory functions are molecularly partitioned, and which degradation machinery couples PCNA binding to turnover, remain unresolved.
  • E3 ligase for PCNA-dependent CDKN1C degradation unidentified
  • Mechanism of growth-promoting function uncharacterized
  • Integration of imprinting, Polycomb, and SWI-SNF inputs at one locus not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2
Partners
CDK7CDK9E2F1PCNAPRDM16

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome and result in loss of PCNA binding. Targeted expression of IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects compared to wild-type CDKN1C, indicating a gain-of-function mechanism. IMAGe mutations are distinct from BWS-causing mutations in CDKN1C. Identity-by-descent analysis, targeted exon capture/sequencing, dideoxy sequencing, Drosophila transgenic overexpression assay Nature genetics High 22634751
2013 IMAGe-associated mutations in the PCNA-binding domain of CDKN1C dramatically increase protein stability via impaired proteasome-mediated degradation, explaining the gain-of-function reduced-growth phenotype. Wild-type CDKN1C is degraded via the proteasome (blocked by MG132), whereas IMAGe mutants (e.g. p.Ile272Ser, p.Asp274Asn, p.Phe276Val) are resistant to degradation. PCNA binding to CDKN1C is disrupted by these mutations. Western blotting with cycloheximide chase, proteasome inhibitor (MG132) treatment, co-immunoprecipitation for PCNA binding PloS one High 24098681 25861374
2015 IMAGe-associated mutations in the PCNA-binding site of CDKN1C significantly increase CDKN1C protein stability and prevent cell cycle progression into S phase. Overexpression of either wild-type or BWS-mutant CDKN1C inhibited cell proliferation, but IMAGe-mutant CDKN1C decreased cell growth significantly more than wild-type or BWS protein. Flow cytometry cell cycle analysis, Western blotting, cell proliferation assays Cell division Medium 25861374
2010 CDKN1C interacts directly with E2F1, CDK7, and CDK9 in vivo and in vitro. CDKN1C is recruited to E2F1-regulated promoters and reduces RNA polymerase II CTD phosphorylation at Ser-2 and Ser-5 in an E2F1-dependent manner. CDKN1C blocks CDK7 and CDK9 ability to phosphorylate a GST-CTD fusion protein in vitro. The E2F1-CDKN1C interaction is mediated by two E2F1 domains. Adenoviral overexpression, RNA interference, chromatin immunoprecipitation (ChIP), in vitro kinase assay with GST-CTD, co-immunoprecipitation in vivo and in vitro The Journal of biological chemistry High 20106982
2008 miR-221 directly targets a site in the 3' UTR of CDKN1C/p57 mRNA to suppress its expression. Transfection of miR-221 into HCC-derived cells downregulates CDKN1C/p57 protein, and antimiR-221 upregulates it, promoting cell growth by increasing S-phase entry. miRNA transfection, antimiR transfection, luciferase reporter assay with 3'UTR, Western blotting, flow cytometry Oncogene High 18521080 21278784
2009 CDKN1C is a direct target of EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3) in breast cancer cells. EZH2 inhibition activates CDKN1C, synergistically enhanced by histone deacetylase inhibitor co-treatment. Chromatin immunoprecipitation (ChIP) for H3K27me3, EZH2 knockdown/inhibition, gene expression analysis PloS one High 19340297 29632530 31367252 33792119
2005 Lsh (a SNF2-family chromatin remodeling protein) directly associates with the 5' differentially methylated region (DMR) at the Cdkn1c promoter by ChIP and controls CpG methylation at this DMR, specifically silencing the paternal Cdkn1c allele. Loss of Lsh reactivates the silenced paternal allele correlating with loss of 5'DMR methylation, without affecting KvDMR1 or other imprinted loci. Chromatin immunoprecipitation (ChIP), allele-specific expression analysis, bisulfite sequencing of CpG methylation in Lsh-deficient mice Development (Cambridge, England) High 15647320
2004 The differentially methylated region (DMR) associated with mouse Cdkn1c is a CpG island beginning 600 bp 5' of the promoter. This methylation is not inherited from sperm but is acquired specifically on the paternal allele after implantation, is dependent on KvDMR1, and is required for maintaining but not establishing monoallelic Cdkn1c expression. Bisulfite sequencing, methylation analysis of gametes and postimplantation embryos, analysis of KvDMR1-deletion mouse model Genomics High 15533713
2005 ZAC (a sequence-specific DNA-binding protein) binds within the CpG island of LIT1 (KCNQ1OT1) and induces LIT1 transcription in a methylation-dependent manner, suggesting ZAC regulates p57KIP2 (CDKN1C) through LIT1 in a novel imprinted gene network. DNA-binding assays, transfection reporter assays, methylation-dependent transcription assays Nucleic acids research Medium 15888726
2001 Enhancers for Cdkn1c expression in skeletal muscle and cartilage lie more than 25 kb downstream of the gene, demonstrating distant cis-regulation. BAC transgenes spanning 315 kb showed no allele-specific expression, suggesting the key imprinting element also lies at a distance from the gene. Bacterial artificial chromosome (BAC) transgenic mouse models, tissue-specific expression analysis Human molecular genetics Medium 11468278
2007 Cdkn1c is the major regulator of embryonic growth within its IC2 imprinted domain in mice. Excess Cdkn1c (via BAC transgene copy number) causes dosage-dependent embryonic growth retardation and lethality associated with reduced Igf1 expression. Loss of Cdkn1c results in 11% heavier embryos with 2-fold increase in Igf1. BAC transgenic mouse models with varying copy numbers, embryonic weight measurements, gene expression analysis BMC developmental biology High 17517131
2011 Cdkn1c mutant mouse embryos exhibit 20% overgrowth during gestation but experience growth reversal late in gestation. Cdkn1c deficiency causes marked placental dysfunction including thrombotic lesions in the labyrinth zone, loss of sinusoidal giant cells, and disordered trilaminar trophoblast layer, identifying a role for Cdkn1c in maintaining the maternal-fetal interface. Mouse genetic model, placental histology, embryonic weight analysis Disease models & mechanisms Medium 21729874
2003 Loss of maternal methylation (LOM) at KvDMR1 in BWS patients causes an 86-93% reduction in CDKN1C expression in fibroblast cells approximately 180 kb away on the maternal chromosome, without hypermethylation at the CDKN1C promoter itself. Quantitative PCR, ribonuclease protection assay, Southern hybridization with methylation-sensitive restriction endonuclease Journal of medical genetics High 14627666
2013 ARX is a direct transcriptional repressor of CDKN1C in cortical progenitor cells. Loss of cortical ARX results in overexpression of CDKN1C, reduced intermediate progenitor cell (IPC) proliferation, and a reduction in upper-layer neurons. Conditional knockout mouse model (cortex-specific Arx cKO), transcriptional profiling, chromatin immunoprecipitation (ChIP) for ARX at Cdkn1c promoter, cortical cell counting Cerebral cortex High 23968833
2012 CDKN1C is a downstream transcriptional target of SMARCB1 and is activated by increased histone H3 and H4 acetylation at its promoter. CDKN1C expression induces cell cycle arrest in rhabdoid tumor cells; siRNA knockdown of CDKN1C increases proliferation and competes against the anti-proliferative effect of restored SMARCB1. The HDAC inhibitor Romidepsin specifically restores CDKN1C expression through promoter histone acetylation. Inducible SMARCB1 expression system, siRNA knockdown, ChIP for histone H3/H4 acetylation at CDKN1C promoter, flow cytometry cell cycle analysis PloS one High 19221586
2018 Targeted demethylation of imprinting control region 2 (ICR2) using a TALE-TET1 fusion protein (ICR2-TET1) reduces CDKN1C/p57 expression and increases proliferation in human fibroblasts and islets. Human islets overexpressing ICR2-TET1 show repressed p57 with upregulated Ki-67 while maintaining glucose-sensing functionality; transplanted epigenetically edited islets show increased β cell replication in diabetic mice. Epigenetic editing with TALE-TET1 fusion, cell proliferation assays, Ki-67 staining, transplantation into diabetic immunodeficient mice The Journal of clinical investigation High 30352048
2018 Cdkn1c is not expressed in quiescent muscle stem cells (MuSCs) but is induced in activated/proliferating myoblasts and maintained in differentiating myogenic cells. Cdkn1c subcellular localization is dynamic: initially cytoplasmic in activated/proliferating myoblasts, then progressively nuclear during differentiation to enforce growth arrest. Cdkn1c-deficient primary myoblasts display differentiation defects and increased proliferation. Mouse molecular genetics (conditional KO), live-cell imaging, subcellular fractionation, immunofluorescence, primary myoblast culture assays eLife High 30284969
2010 Cdkn1c is induced by Hedgehog signaling in slow muscle precursor cells in zebrafish and cooperates with Myod to drive terminal differentiation of multiple early muscle fiber types. Myod in turn upregulates cdkn1c, forming a positive feedback loop that switches myogenic cells to terminal differentiation. Neither Hedgehog nor Cdkn1c is required for cell cycle exit per se. Zebrafish genetic analysis, morpholino knockdown, immunostaining, in situ hybridization, epistasis analysis Developmental biology High 21147088
2005 Cdkn1c is a downstream target of MyoD during myogenic differentiation in C2C12 cells. MyoD-silenced clones show altered Cdkn1c expression, and bioinformatic and functional promoter studies demonstrate Cdkn1c dependence on MyoD activity. MyoD-silenced C2C12 clone generation, cDNA microarray, promoter functional analysis, quantitative PCR Journal of molecular biology Medium 15890200
2015 Paternal allelic mutation at the Kcnq1 locus reduces Kcnq1ot1 expression and increases Cdkn1c expression specifically on the paternal allele, reducing pancreatic β-cell mass. Histone modifications at the Cdkn1c promoter region in pancreatic islets contribute to this epigenetic regulation. Genetically modified mice (paternal vs maternal transmission), quantitative RT-PCR, histone modification ChIP in pancreatic islets, β-cell mass measurements Proceedings of the National Academy of Sciences of the United States of America High 26100882
2016 Cdkn1c is required for development of the brown adipose lineage. Loss-of-function of Cdkn1c results in complete developmental failure of the brown adipocyte lineage. Cdkn1c is required for post-transcriptional accumulation of the brown fat determinant PRDM16, and CDKN1C and PRDM16 co-localize to the nucleus of rare label-retaining cells within interscapular brown adipose tissue. Mouse genetic models (gain and loss of function Cdkn1c), brown adipose tissue histology, immunostaining, ex vivo differentiation assays, co-localization imaging PLoS genetics High 26963625
2020 Cdkn1c has a cell-autonomous growth-promoting function in radial glial progenitor cells and nascent projection neurons in the cerebral cortex, mediating their survival. This is distinct from its non-cell-autonomous growth-inhibitory function. The growth-promoting function is dosage-sensitive but not subject to genomic imprinting. Mosaic Analysis with Double Markers (MADM) technology for single-cell resolution genetic dissection, cell counting, clonal analysis Nature communications High 31924768
2019 CDYL recruits EZH2 to the CDKN1C promoter region to regulate H3K27 trimethylation, causing transcriptional silencing of CDKN1C and promoting chemoresistance in small cell lung cancer. The CDYL/EZH2/CDKN1C axis was established by ChIP-qPCR, co-immunoprecipitation, GST pull-down, and EMSA assays. ChIP-qPCR, co-immunoprecipitation, GST pull-down, EMSA, mRNA sequencing, Western blotting, in vivo tumor models Theranostics High 31367252
2017 Acute exposure to chromatin-modifying drugs causes temporary de-repression of the paternal (silent) Cdkn1c allele in mouse embryos. Chronic in utero maternal dietary protein deprivation causes permanent de-repression of imprinted Cdkn1c expression through a folate-dependent mechanism of DNA methylation loss at the paternal allele, sustained into adulthood. Allele-specific bioluminescent reporters (Cdkn1c-luciferase mice), in vivo live imaging, DNA methylation analysis, dietary manipulation studies Cell reports High 28147266
2020 The paternal allele of Cdkn1c is expressed at a low level in the developing mouse neocortex. CNS-specific conditional deletion of the paternal allele results in marked reduction in brain size and reduction in neural stem-progenitor cell (NPC) number during neocortical development, reducing upper-layer neuron production. Conditional allele-specific KO mice (CNS-Cre for paternal allele), brain size measurement, immunostaining, NPC counting Scientific reports Medium 32024956
2023 IGF2 promotes terminal differentiation of neural stem cells (NSCs) into astrocytes, neurons, and oligodendrocytes by inducing Cdkn1c/p57 expression. Using intraventricular infusion of recombinant IGF2 in Cdkn1c-deficient NSC conditional mutants, p57 was confirmed to partially mediate IGF2's differentiation effects independently of its role in cell-cycle progression. Conditional KO of Cdkn1c in NSCs, intraventricular infusion of recombinant IGF2, lineage analysis, genetic epistasis Development (Cambridge, England) High 36633189
2013 CDKN1C mutation p.Arg279Leu in the PCNA-binding domain causes familial RSS phenotype. Functional analysis showed this mutation did not affect the cell cycle (unlike IMAGe mutations), but led to increased CDKN1C protein stability. The IMAGe mutation p.Arg279Pro caused gain-of-function cell cycle effects. Flow cytometry cell cycle analysis, Western blotting with cycloheximide to assess stability, Sanger sequencing Journal of medical genetics Medium 24065356
2017 Cdkn1c elevated expression in the brain (in a transgenic loss-of-imprinting model) leads to altered dopaminergic gene expression, increased tyrosine hydroxylase staining, and increased dopamine tissue content in the striatum, indicating a functional role for Cdkn1c dosage in midbrain dopaminergic neuron development and behavior. Cdkn1c BAC transgenic (Cdkn1cBACx1) mouse model, tyrosine hydroxylase immunostaining, HPLC dopamine quantification, c-fos expression, behavioral assays Genes, brain, and behavior Medium 28857482
2012 Hes1 (a Notch effector) directly represses CDKN1C/P57 transcription in hepatocellular carcinoma cells. Downregulation of Notch1/3 leads to Hes1 downregulation and CDKN1C/P57 upregulation. CDKN1C/P57 upregulation induces cellular senescence (senescence-associated β-galactosidase accumulation, P16 increase, morphological changes) without affecting apoptosis. siRNA knockdown of Notch1/Notch3/Hes1, cDNA transfection of CDKN1C, flow cytometry, senescence-associated β-galactosidase assay, Western blotting The American journal of pathology Medium 22705236
2019 miR-222 derived from M1 macrophage exosomes promotes vascular smooth muscle cell (VSMC) proliferation and migration by targeting CDKN1C (and CDKN1B). These exosomes are taken up by VSMCs through macropinocytosis, and miR-222 inhibitor abolishes this effect in vitro and in vivo. Transwell co-culture, exosome isolation, microRNA array, luciferase reporter assay for 3'UTR targeting, carotid artery ligation model, miR-222 inhibitor treatment Cell death & disease Medium 31142732
2018 Ezh2 represses Cdkn1c (and Cdkn2a) in activated naive CD8+ T cells by H3K27me3 at these gene loci. Deletion of Ezh2 in CD8+ T cells increases Cdkn1c and Cdkn2a expression and impairs activation-induced proliferation with prolonged cell division times. Conditional Ezh2 KO mice (Ezh2fl/fl Cd4Cre+ and GzmBCre+), ChIP for H3K27me3, quantitative PCR, real-time live imaging of cell division Frontiers in immunology High 29632530
2021 MBD2 (a DNA methylation reader) promotes leukemic stem cell (LSC) cycle progression through epigenetic regulation of CDKN1C transcription by binding to its promoter region. Loss of MBD2 delays MLL-AF9-driven leukemia initiation and progression via increased CDKN1C expression. MBD2 knockout in MLL-AF9 murine leukemia model, serial transplantation, gene expression analysis, bioinformatics, MBD2 ChIP at CDKN1C promoter Oncogenesis Medium 34789717
2015 miR-25 directly targets the 3'UTR of CDKN1C to reduce its protein levels, increasing glioma cell proliferation. Ablation of endogenous miR-25 rescues CDKN1C expression and decreases glioma cell proliferation. Downregulation of CDKN1C by siRNA blocked the antiproliferative activity of miR-25 inhibition. 3'UTR luciferase reporter assay, miR-25 overexpression/knockdown, siRNA, cell proliferation assays, flow cytometry Biomedicine & pharmacotherapy Medium 25960208
2017 The T2DM-associated SNP rs163184 in the KCNQ1 intronic region modulates binding of Sp3 and Lsd1/Kdm1a in an allele-specific manner. Sp3 binds preferentially to the non-risk allele and stimulates transcriptional activity. Lsd1/Kdm1a is preferentially recruited to the non-risk allele and reduces Sp3-dependent transcriptional activity. SP3 knockdown upregulates CDKN1C expression in cells with non-risk alleles. DNA pulldown with allele-specific probes, mass spectrometry protein identification, artificial promoter reporter assay, SP3 siRNA knockdown, gene expression analysis International journal of molecular medicine Medium 29207083
2016 CTCF binding sites are present within the unmethylated CDKN1C gene body CpG island in human placenta. Putative enhancer regions containing H3K4me1 and H3K27ac marks are located approximately 58 and 360 kb from CDKN1C. 3C-PCR identifies constitutive higher-order chromatin loops between one of these enhancer regions and CDKN1C in human placenta. Chromatin immunoprecipitation (ChIP) for CTCF and histone marks, Chromosome Conformation Capture (3C-PCR) Frontiers in genetics Medium 27200075

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 527 18521080
2009 CDKN1C (p57) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cells. PloS one 143 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 139 10424811
2012 Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nature genetics 132 22634751
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
2003 Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith-Wiedemann syndrome. Journal of medical genetics 123 14627666
2013 CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. Journal of medical genetics 104 24065356
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
2000 Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression. Human molecular genetics 101 10607831
1993 Molecular characterization of cytogenetic alterations associated with the Beckwith-Wiedemann syndrome (BWS) phenotype refines the localization and suggests the gene for BWS is imprinted. Human molecular genetics 92 8518793
2011 The hallmarks of CDKN1C (p57, KIP2) in cancer. Biochimica et biophysica acta 91 21447370
2007 Cdkn1c (p57Kip2) is the major regulator of embryonic growth within its imprinted domain on mouse distal chromosome 7. BMC developmental biology 82 17517131
2011 MicroRNA-221 inhibits CDKN1C/p57 expression in human colorectal carcinoma. Acta pharmacologica Sinica 78 21278784
2011 Fetal overgrowth in the Cdkn1c mouse model of Beckwith-Wiedemann syndrome. Disease models & mechanisms 78 21729874
2014 CDKN1C mutations: two sides of the same coin. Trends in molecular medicine 77 25262539
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
2008 MS-MLPA is a specific and sensitive technique for detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment. European journal of human genetics : EJHG 66 18212817
2001 Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors. European journal of endocrinology 65 11454518
2001 Distant cis-elements regulate imprinted expression of the mouse p57( Kip2) (Cdkn1c) gene: implications for the human disorder, Beckwith--Wiedemann syndrome. Human molecular genetics 64 11468278
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 62 20503313
2015 Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization. Human mutation 61 26077438
2005 Lsh controls silencing of the imprinted Cdkn1c gene. Development (Cambridge, England) 60 15647320
2004 Methylation at mouse Cdkn1c is acquired during postimplantation development and functions to maintain imprinted expression. Genomics 59 15533713
2019 Exosomes derived from M1 macrophages aggravate neointimal hyperplasia following carotid artery injuries in mice through miR-222/CDKN1B/CDKN1C pathway. Cell death & disease 58 31142732
2012 CDKN1C/P57 is regulated by the Notch target gene Hes1 and induces senescence in human hepatocellular carcinoma. The American journal of pathology 58 22705236
2004 Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith-Wiedemann syndrome (BWS). The Journal of pediatrics 57 15580204
2018 Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases. International journal of molecular sciences 55 29614816
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 54 26100882
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
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 52 30352048
2008 CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer. BMC cancer 52 18325103
2018 Ezh2 Regulates Activation-Induced CD8+ T Cell Cycle Progression via Repressing Cdkn2a and Cdkn1c Expression. Frontiers in immunology 51 29632530
2009 Imprinted CDKN1C is a tumor suppressor in rhabdoid tumor and activated by restoration of SMARCB1 and histone deacetylase inhibitors. PloS one 49 19221586
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
2001 Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations. Genomics 47 11414765
2006 Imprinting disruption of the CDKN1C/KCNQ1OT1 domain: the molecular mechanisms causing Beckwith-Wiedemann syndrome and cancer. Cytogenetic and genome research 46 16575194
2018 Cellular localization of the cell cycle inhibitor Cdkn1c controls growth arrest of adult skeletal muscle stem cells. eLife 42 30284969
2019 CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter. Theranostics 41 31367252
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
2012 Expression of KCNQ1OT1, CDKN1C, H19, and PLAGL1 and the methylation patterns at the KvDMR1 and H19/IGF2 imprinting control regions is conserved between human and bovine. Journal of biomedical science 39 23153226
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 LncRNA-BLACAT1 Facilitates Proliferation, Migration and Aerobic Glycolysis of Pancreatic Cancer Cells by Repressing CDKN1C via EZH2-Induced H3K27me3. Frontiers in oncology 37 33072570
2009 CDKN1C mutations in HELLP/preeclamptic mothers of Beckwith-Wiedemann Syndrome (BWS) patients. Placenta 37 19386358
2021 Long non-coding RNA linc00665 inhibits CDKN1C expression by binding to EZH2 and affects cisplatin sensitivity of NSCLC cells. Molecular therapy. Nucleic acids 36 33664990
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
2010 Cdkn1c drives muscle differentiation through a positive feedback loop with Myod. Developmental biology 36 21147088
1995 Genome-wide loss of maternal alleles in a nephrogenic rest and Wilms' tumour from a BWS patient. Human genetics 36 7789950
2017 KLF15 Inhibits Cell Proliferation in Gastric Cancer Cells via Up-Regulating CDKN1A/p21 and CDKN1C/p57 Expression. Digestive diseases and sciences 35 28421457
2013 Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome. PloS one 33 24098681
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
2011 An 11p15 imprinting centre region 2 deletion in a family with Beckwith Wiedemann syndrome provides insights into imprinting control at CDKN1C. PloS one 31 22205991
2007 Role of the CDKN1A/p21, CDKN1C/p57, and CDKN2A/p16 genes in the risk of atherosclerosis and myocardial infarction. Cell cycle (Georgetown, Tex.) 31 17351341
2014 Expression profiling of long noncoding RNAs and the dynamic changes of lncRNA-NR024118 and Cdkn1c in angiotensin II-treated cardiac fibroblasts. International journal of clinical and experimental pathology 29 24817929
2008 Evolution of the CDKN1C-KCNQ1 imprinted domain. BMC evolutionary biology 29 18510768
2014 Methylation analysis in tongue tissue of BWS patients identifies the (EPI)genetic cause in 3 patients with normal methylation levels in blood. European journal of medical genetics 27 24704790
2009 A case of Beckwith-Wiedemann syndrome caused by a cryptic 11p15 deletion encompassing the centromeric imprinted domain of the BWS locus. Journal of medical genetics 27 19843502
2005 The Ankrd2, Cdkn1c and calcyclin genes are under the control of MyoD during myogenic differentiation. Journal of molecular biology 26 15890200
2016 Cdkn1c Boosts the Development of Brown Adipose Tissue in a Murine Model of Silver Russell Syndrome. PLoS genetics 25 26963625
2016 Epigenetic Characterization of CDKN1C in Placenta Samples from Non-syndromic Intrauterine Growth Restriction. Frontiers in genetics 24 27200075
2015 Losartan reverses the down-expression of long noncoding RNA-NR024118 and Cdkn1c induced by angiotensin II in adult rat cardiac fibroblasts. Pathologie-biologie 24 25979571
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
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
1997 Novel transcribed sequences within the BWS/WT2 region in 11p15.5: tissue-specific expression correlates with cancer type. Genomics 22 9441738
2023 PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDKN1C and SMC1A. Cancer medicine 20 37212524
2020 lncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer. Molecular therapy. Nucleic acids 20 32679543
2019 Targeting EZH1/2 induces cell cycle arrest and inhibits cell proliferation through reactivation of p57CDKN1C and TP53INP1 in mantle cell lymphoma. Cancer biology & medicine 20 31565482
2017 Dopaminergic and behavioural changes in a loss-of-imprinting model of Cdkn1c. Genes, brain, and behavior 20 28857482
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
2015 Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase. Cell division 19 25861374
2013 Knockdown of CDKN1C (p57(kip2)) and PHLDA2 results in developmental changes in bovine pre-implantation embryos. PloS one 19 23894493
2000 Analysis of CDKN1C in Beckwith Wiedemann syndrome. Human mutation 19 10862080
2023 IGF2 interacts with the imprinted gene Cdkn1c to promote terminal differentiation of neural stem cells. Development (Cambridge, England) 18 36633189
2019 Analysis of CDKN1C in fetal growth restriction and pregnancy loss. F1000Research 18 31497289
1999 CDKN1C expression in Beckwith-Wiedemann syndrome patients with allele imbalance. Journal of medical genetics 18 10424812
2010 Autonomous silencing of the imprinted Cdkn1c gene in stem cells. Epigenetics 17 20372090
2005 Alternative mechanisms associated with silencing of CDKN1C in Beckwith-Wiedemann syndrome. Journal of medical genetics 17 16061564
2020 Novel mutation points to a hot spot in CDKN1C causing Silver-Russell syndrome. Clinical epigenetics 16 33076988
2017 Maternal high estradiol exposure alters CDKN1C and IGF2 expression in human placenta. Placenta 16 29277274
2014 Silver-Russell syndrome without body asymmetry in three patients with duplications of maternally derived chromosome 11p15 involving CDKN1C. Journal of human genetics 16 25427884
2020 Silencing of microRNA-517a induces oxidative stress injury in melanoma cells via inactivation of the JNK signaling pathway by upregulating CDKN1C. Cancer cell international 15 32015692
2019 Familial Russell-Silver Syndrome like Phenotype in the PCNA Domain of the CDKN1C Gene, a Further Case. Case reports in genetics 15 31976094
2016 Parent-of-origin tumourigenesis is mediated by an essential imprinted modifier in SDHD-linked paragangliomas: SLC22A18 and CDKN1C are candidate tumour modifiers. Human molecular genetics 15 27402879
2021 miR-92b-3p Regulates Cell Cycle and Apoptosis by Targeting CDKN1C, Thereby Affecting the Sensitivity of Colorectal Cancer Cells to Chemotherapeutic Drugs. Cancers 14 34283053
2020 Role of the imprinted allele of the Cdkn1c gene in mouse neocortical development. Scientific reports 14 32024956
2011 Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression. Genomics 14 22079941
2005 p57Kip2 (cdkn1c): sequence, splice variants and unique temporal and spatial expression pattern in the rat pancreas. Laboratory investigation; a journal of technical methods and pathology 14 15696192
1990 Molecular characterization of Beckwith-Wiedemann syndrome (BWS) patients with partial duplication of chromosome 11p excludes the gene MYOD1 from the BWS region. Genomics 14 2276740
2018 Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation. Oncogenesis 13 30310057
2007 Cell cycle genes PEDF and CDKN1C in growing deer antlers. Anatomical record (Hoboken, N.J. : 2007) 13 17610257
2022 Epigenetic control of the imprinted growth regulator Cdkn1c in cadmium-induced placental dysfunction. Epigenetics 12 35770551
2021 Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C. Oncogenesis 12 34789717
2017 A type 2 diabetes-associated SNP in KCNQ1 (rs163184) modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a, potentially affecting CDKN1C expression. International journal of molecular medicine 12 29207083
2023 Lappaol F regulates the cell cycle by activating CDKN1C/p57 in human colorectal cancer cells. Pharmaceutical biology 11 36708218
2017 IMAGe and Related Undergrowth Syndromes: The Complex Spectrum of Gain-of-Function CDKN1C Mutations. Pediatric endocrinology reviews : PER 11 28508599

Missed literature

Know a paper Affinage missed for CDKN1C? Flag it for the maintainers and the community.

No submissions yet.