Affinage

CDKN2C

Cyclin-dependent kinase 4 inhibitor C · UniProt P42773

Length
168 aa
Mass
18.1 kDa
Annotated
2026-06-09
90 papers in source corpus 37 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKN2C/p18(INK4c) is an ankyrin-repeat CDK inhibitor that enforces G1 cell cycle exit by binding CDK4 and CDK6 to suppress their kinase activity, thereby maintaining Rb in its hypophosphorylated, growth-suppressive state across diverse differentiating tissues (PMID:9052836, PMID:15349907, PMID:39426133). It engages CDK6 upon IL-6 stimulation to couple cell cycle arrest to terminal B cell/plasma cell differentiation (PMID:9052836, PMID:12196289), and cooperates with the Cip/Kip inhibitors p27 and p21 in genetically separable pathways that restrain proliferation in the pituitary, liver, and other tissues, in part by redistributing CDK-inhibitor complexes to secondarily lower cyclin E-CDK2 activity (PMID:9744866, PMID:10713180, PMID:12668976). Through this CDK4/6-Rb axis p18 acts as a nodal tumor suppressor whose loss or repression drives proliferation and tumorigenesis: it restrains hematopoietic stem cell self-renewal (PMID:16234365), limits mammary luminal progenitor expansion (PMID:19411068), and is haploinsufficient within the Shh/Patched pathway in medulloblastoma (PMID:16260494). Its dosage is set at two levels. Post-translationally, p18 stability is governed by polyubiquitination at preferred lysines K46 and K112; CDK4/6 binding shields p18 from ubiquitination and stabilizes it, while cyclin D1 competes for CDK binding and accelerates p18 turnover (PMID:19029828). Transcriptionally, p18 is repressed by a convergent set of factors and chromatin modifiers, including direct GATA3 binding (in complex with Ruvbl2) (PMID:19411068, PMID:24167278), oncogenic MAPK-driven repression via AP-1/c-Jun and N-Myc (PMID:21112821, PMID:22997239), PML/RARα at the promoter (PMID:27888400), and Polycomb/heterochromatin marks deposited by EZH2 (H3K27me3, via LINC00673), CBX8 (H2AK119ub), and SETDB2 (H3K9me3, downstream of E2A-PBX1) (PMID:29694893, PMID:33014799, PMID:37733753). p18 also functions as a cell-intrinsic restrictor of gammaherpesvirus reactivation, an activity specifically bypassed by the viral cyclin (PMID:26292318, PMID:29298882).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1997 High

    Established that p18(INK4c) physically engages CDK6 and links cytokine signaling to cell cycle arrest, defining its core molecular activity in differentiation.

    Evidence Co-IP and overexpression in IL-6-stimulated B lymphoblastoid cells with pRb phosphorylation readout

    PMID:9052836

    Open questions at the time
    • Did not distinguish CDK6 versus CDK4 preference in other contexts
    • Endogenous regulation of p18 induction by IL-6 not mapped
  2. 1998 High

    Demonstrated that p18 suppresses tumorigenesis through a pathway genetically separable from p27, showing it is a non-redundant in vivo tumor suppressor.

    Evidence Single and double knockout mouse genetics with pituitary adenoma histopathology

    PMID:9744866

    Open questions at the time
    • Molecular basis of the p18/p27 division of labor at the CDK level not fully resolved here
  3. 1999 High

    Resolved how p18 differs biophysically from related INK4 proteins, showing greater kinetic stability of its ankyrin-repeat fold.

    Evidence NMR H/2H exchange and chemical denaturation of p18 versus p16/p15

    PMID:10556039

    Open questions at the time
    • Conformational stability not directly tied to CDK-binding affinity or in-cell function
  4. 2000 High

    Clarified that p18 cooperates with p27 not by directly inhibiting CDK2 but by redistributing inhibitor complexes, explaining secondary suppression of cyclin E-CDK2.

    Evidence In vitro kinase assays with recombinant proteins, Co-IP, and gel filtration in progestin-arrested cells

    PMID:10713180

    Open questions at the time
    • Quantitative stoichiometry of complex redistribution in vivo not established
  5. 2001 High

    Extended p18 function to germ cell and Leydig cell proliferation control, showing tissue-specific requirements in spermatogenesis.

    Evidence Single/double p18/p19 knockout mouse genetics with hormone assays and cell cycle analysis

    PMID:11287627

    Open questions at the time
    • CDK partner mediating the spermatogonial and Leydig phenotypes not pinpointed
  6. 2002 High

    Showed p18 is required cell-intrinsically in B cells for terminal plasma cell differentiation and antibody secretion, cementing its differentiation-arrest role.

    Evidence Knockout mouse immunization with ELISA antibody titers, histology, flow cytometry

    PMID:12196289

    Open questions at the time
    • Transcriptional trigger of p18 during plasma cell commitment not defined
  7. 2003 Medium

    Identified p18 as a downstream effector of oncogenic kinase inhibition and as a collaborator with Cip/Kip inhibitors in regenerative proliferation, broadening its signaling context.

    Evidence Antisense knockdown in ETV6/ARG leukemia cells; p18/p21 and p18/p27 double-knockout partial hepatectomy models

    PMID:12668976 PMID:12821941

    Open questions at the time
    • Single-cell-line antisense without reciprocal validation
    • Direct vs indirect link between ARG kinase and p18 transcription unresolved
  8. 2004 Medium

    Established context-dependent CDK partner choice and the first promoter-level repression mechanism, showing p18 preferentially binds CDK4 in HCC and is suppressed by PKC signaling.

    Evidence Co-IP plus CDK4/CDK6 kinase assays in HCC tumors; siRNA, promoter reporters, and PKC inhibition in cancer cells

    PMID:15107819 PMID:15349907

    Open questions at the time
    • The PKC-responsive promoter element/transcription factor not identified
    • AP-1-independence mechanism left open
  9. 2005 High

    Defined p18 as a dosage-sensitive tumor suppressor within the Shh pathway and as a restraint on hematopoietic stem cell self-renewal, revealing stem/progenitor roles.

    Evidence Ink4c+/-/Ptc1+/- compound genetics with LOH and human medulloblastoma methylation; serial bone marrow transplantation of p18-null HSCs

    PMID:16234365 PMID:16260494

    Open questions at the time
    • How p18 intersects Shh signaling molecularly not detailed
    • Mechanism of p18/p21 antagonism in HSC senescence not resolved
  10. 2006 Medium

    Connected oncogenic RET/MAPK and Rb-pathway output to p18 regulation, showing p18 repression is both an effector of and feedback node for proliferative signaling.

    Evidence Inducible RET2A with MEK inhibition and tumor profiling; p18/Pten double-mutant mice with phospho-Akt readouts

    PMID:16738322 PMID:16953232

    Open questions at the time
    • Direct transcriptional mediator of RET-driven p18 repression not yet identified (resolved later by N-Myc)
    • Mechanism of Rb-to-Akt feedback indirect
  11. 2008 High

    Defined the post-translational control of p18 abundance and its functional sufficiency as a senescence-inducing tumor suppressor, and identified an Sp1/acetylation-dependent activation route.

    Evidence In vitro ubiquitination with K-to-R mutagenesis and half-life measurement; lentiviral reconstitution in GBM cells; ChIP and Sp1-site promoter mutagenesis in K562

    PMID:18381405 PMID:18642058 PMID:19029828

    Open questions at the time
    • Identity of the physiological E3 ligase for K46/K112 ubiquitination not established
    • Cofactor coupling Sp1 to acetylation not defined
  12. 2009 High

    Identified GATA3 as a direct transcriptional repressor of INK4C, mechanistically linking luminal progenitor expansion and ER+ mammary tumorigenesis to p18 loss.

    Evidence ChIP, luciferase reporter, and loss-of-function mouse genetics in mammary tissue

    PMID:19411068

    Open questions at the time
    • Cofactor requirement for GATA3 repression not yet defined (later linked to Ruvbl2)
  13. 2010 Medium

    Pinpointed N-Myc as the direct MAPK-induced repressor at the p18 promoter, completing the RET2A→MAPK→N-Myc→p18 repression axis.

    Evidence N-Myc promoter ChIP, dominant-negative/knockdown, reporter assays, and MEK inhibition

    PMID:21112821

    Open questions at the time
    • Single-lab promoter study; generality across N-Myc-driven tumors untested
  14. 2011 Medium

    Showed a hypomorphic Cdkn2c promoter allele drives autoimmune B1a cell expansion, establishing p18 dosage as a disease-relevant determinant of B cell proliferation.

    Evidence Genetic mapping, promoter SNP identification, and B cell cell-cycle assays in the lupus Sle2c1 locus

    PMID:21543644

    Open questions at the time
    • Mechanism by which the promoter SNP lowers expression not detailed
  15. 2012 Medium

    Demonstrated AP-1/c-Jun-mediated CDKN2C repression downstream of BRAF/NRAS as a therapeutic vulnerability, supporting combined CDK and MAPK inhibition.

    Evidence Dominant-negative c-Jun, proliferation assays, and xenografts in melanoma

    PMID:22997239

    Open questions at the time
    • Direct AP-1 binding at the CDKN2C promoter not shown here
  16. 2013 High

    Revealed the GATA3-Ruvbl2 complex as the repressive machinery at Cdkn2c and extended this control to Th2 proliferation, and localized p18-CDK4 interaction to the cytosol in quiescent beta-cells.

    Evidence Gata3/Ruvbl2 Co-IP, ChIP, and Cdkn2c-knockdown rescue in Th2 cells; Co-IP and confocal fractionation in human beta-cells

    PMID:23896637 PMID:24167278

    Open questions at the time
    • Functional significance of cytosolic p18 localization not directly tested
    • Whether GATA3-Ruvbl2 operates identically in mammary tissue untested
  17. 2015 Medium

    Provided pharmacological proof that inhibiting p18 expands functional HSCs, validating p18 as a druggable restraint on stem cell self-renewal.

    Evidence Structure-based in silico screening, SAR, HSC expansion assays, and competitive repopulation

    PMID:25692908 PMID:26681454

    Open questions at the time
    • Direct binding mode of inhibitors to p18 and on-target specificity in vivo not fully resolved
  18. 2016 High

    Established p18 as a cell-intrinsic restrictor of gammaherpesvirus reactivation, with a viral cyclin specifically bypassing it, and identified additional epigenetic repressors and a localization correlate in leukemia.

    Evidence p18 knockout/knock-in recombinant virus reactivation assays; PML/RARα ChIP and reporter with ATRA in APL; p18 immunofluorescence/fractionation in CML LSCs

    PMID:26292318 PMID:26985855 PMID:27888400 PMID:29298882

    Open questions at the time
    • How p18 restricts reactivation mechanistically beyond CDK inhibition not defined
    • CML localization study lacks direct functional manipulation
  19. 2018 High

    Defined the E2A-PBX1→SETDB2→H3K9me3 axis silencing CDKN2C, identifying heterochromatin-mediated repression as a leukemia maintenance mechanism.

    Evidence H3K9me3 and E2A-PBX1 ChIP, SETDB2 knockdown, and in vivo leukemia maintenance assays in pre-BCR+ ALL

    PMID:29694893

    Open questions at the time
    • Whether other INK4 loci are co-regulated by this axis not addressed
  20. 2020 Medium

    Expanded the repressive epigenetic repertoire (EZH2/H3K27me3 via LINC00673) and uncovered a proviral role in which CDKN2C-driven G1 arrest supports HBV replication.

    Evidence H3K27me3 ChIP, EZH2 inhibition, siRNA in cancer cells; genome-wide gain-of-function screen and viral replication assays in primary hepatocytes

    PMID:32483149 PMID:33014799

    Open questions at the time
    • Mechanistic link between G1 arrest and HBV enhancer activity incompletely defined
  21. 2022 Medium

    Showed INK4 binding shields CDK6 from targeted degradation, revealing p18 levels as a determinant of CDK6-PROTAC resistance.

    Evidence CDK6 PROTAC treatment, Co-IP, and proliferation assays in AML cell lines

    PMID:35326705

    Open questions at the time
    • Structural basis of degrader shielding not resolved
  22. 2023 Medium

    Added CBX8/H2AK119ub as a Polycomb repressor of CDKN2C driving lung adenocarcinoma growth, reinforcing the epigenetic-silencing theme.

    Evidence CBX8 and H2AK119ub ChIP, knockdown/overexpression, and CDKN2C-knockdown rescue with RNA-seq

    PMID:37733753

    Open questions at the time
    • Interplay among the multiple repressive marks at CDKN2C not integrated
  23. 2024 Medium

    Demonstrated CDKN2C confers radiosensitivity via CDK4-Thr172/pRb suppression and identified oxidized miR-30c as a post-transcriptional repressor, broadening the regulatory and therapeutic landscape.

    Evidence Lentiviral overexpression with phospho-CDK4/pRb readouts and xenografts in osteosarcoma; luciferase and O8G miRNA IP in cardiac fibrosis models

    PMID:38849466 PMID:39426133

    Open questions at the time
    • Whether CDK4-selective effect generalizes beyond osteosarcoma untested
    • Endogenous prevalence of oxidized miR-30c targeting CDKN2C in human disease unclear
  24. 2025 Low

    Proposed RNF149 as a ubiquitin ligase acting on CDKN2C in HNSC, addressing which E3 controls p18 turnover.

    Evidence Proximity ligation assay, Co-IP, knockdown, and tissue arrays in head and neck squamous carcinoma

    PMID:42049330

    Open questions at the time
    • No direct ubiquitin transfer assay demonstrating RNF149 catalyzes p18 ubiquitination
    • Single lab without reciprocal in vivo validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • The physiological E3 ligase(s) executing the K46/K112 polyubiquitination that sets p18 half-life, and how the many transcriptional/epigenetic repressors are coordinated in a given lineage, remain unresolved.
  • No validated endogenous E3 ligase for K46/K112 ubiquitination
  • No structural model of the p18-CDK4/6 complex described in the corpus
  • Combinatorial logic of GATA3, Polycomb, SETDB2, and MAPK-driven repressors not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 7 R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 4
Partners
CCND1CDK4CDK6CDKN1BGATA3RNF149RUVBL2

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 p18(INK4c) associates with CDK6 upon IL-6 stimulation in B lymphoblastoid cells, suppressing CDK6 activity and thereby inhibiting pRb phosphorylation, leading to cell cycle arrest coupled to terminal B cell differentiation. Co-immunoprecipitation, Western blot, overexpression in lymphoblastoid cells, flow cytometry Immunity High 9052836
1998 p18(INK4c) and p27(Kip1) mediate two genetically separable pathways to suppress pituitary tumorigenesis; mice lacking both develop pituitary adenomas with near-complete penetrance by 3 months, while single knockouts develop adenomas more slowly, indicating non-redundant collaborative tumor suppression likely through controlling Rb function. Genetic epistasis — single and double knockout mouse models, histopathology, proliferation assays Genes & development High 9744866
1999 p18(INK4C) and p16(INK4A) share the ankyrin-repeat fold but differ in conformational stability: p18 has a subset of very slowly exchanging amide protons (especially in the fourth ankyrin repeat region) indicating greater kinetic stability than p16 and p15, which correlates with lower aggregation tendency. NMR (H/2H exchange, heteronuclear NOE), chemical denaturation Journal of molecular biology High 10556039
2000 p18(INK4c) cooperates with p27(Kip1) to inhibit cyclin E-CDK2 and CDK4/6 in progestin-mediated cell cycle arrest: p27 directly inhibits cyclin E-CDK2 whereas p18 binds CDK4/CDK6 and, through redistribution of CDK inhibitor complexes, secondarily reduces cyclin E-CDK2 activity. In vitro kinase assay with recombinant His6-p27 and recombinant p18(INK4c), co-immunoprecipitation, gel filtration chromatography, Western blot Molecular and cellular biology High 10713180
2001 Combined loss of p18(Ink4c) and p19(Ink4d) in male mice causes infertility by impairing mitotic exit of spermatogonia and blocking meiotic maturation of spermatocytes; loss of p18 alone causes Leydig cell hyperplasia with reduced testosterone production independent of LH levels. Single and double knockout mouse genetics, histopathology, hormone assays (LH, FSH, testosterone), cell cycle analysis Molecular and cellular biology High 11287627
2002 p18(INK4c) is required within B cells for terminal plasma cell differentiation and cell cycle arrest; p18-deficient mice show B cell hyperproliferation in germinal centers despite normal class switch, hypermutation, and plasmacytoid differentiation, but severely reduced antibody secretion, placing p18 as a requisite CDK6 inhibitor for functional plasma cell generation. Conditional/germline knockout mouse model, immunization, ELISA for antibody titers, histology, flow cytometry Immunity High 12196289
2003 p18(INK4c) upregulation by STI571 is required for G1 arrest in ETV6/ARG-expressing leukemia cells; antisense knockdown of Ink4c abrogates STI571-induced growth inhibition, demonstrating that p18 is a downstream effector of ARG kinase suppression. Antisense oligonucleotide knockdown, cell cycle analysis (flow cytometry), Western blot, cell fractionation Oncogene Medium 12821941
2003 p18(INK4c) collaborates with p21(CIP1) to control G1 timing and with p27(KIP1) to limit hepatocyte DNA synthesis after partial hepatectomy; double knockouts of p18/p21 show earlier CDK activation and earlier G1 exit, while p18/p27 double knockouts show elevated hepatocyte proliferation at 48 hours. Single and double knockout mouse models, partial hepatectomy, BrdU/PCNA labeling, Western blot for cell cycle proteins Hepatology Medium 12668976
2004 In p18(INK4c)-positive hepatocellular carcinomas, p18 preferentially associates with CDK4 rather than CDK6, leading to reduced CDK4 kinase activity and less pRb phosphorylation at Ser780 compared with p18-negative tumors. Co-immunoprecipitation, in vitro CDK4/CDK6 kinase assay, Western blot with phospho-Rb antibody, immunohistochemistry Hepatology Medium 15349907
2004 PKC activation by TPA suppresses p18(INK4c) expression at the promoter level in an AP-1-independent manner, and siRNA knockdown of p18 enhances cancer cell growth, demonstrating that p18 is a critical PKC-regulated growth-inhibitory target. siRNA knockdown, promoter reporter assays, PKC inhibitor (Ro 31-8425), dominant-negative c-Jun expression, cell growth assay Oncogene Medium 15107819
2005 Ink4c is haploinsufficient for tumor suppression when combined with Patched (Ptc1) heterozygosity; tumors in Ink4c+/-/Ptc1+/- mice retain wild-type Ink4c but lose wild-type Ptc1, and methylation of INK4C is found in 4/23 human medulloblastomas with absent p18 protein in 14/73 cases, placing Ink4c in the Shh pathway for cerebellar granule cell cycle exit. Compound heterozygous mouse genetics, LOH analysis, methylation analysis, immunohistochemistry, in situ hybridization Genes & development High 16260494
2005 Loss of p18(INK4c) enhances long-term hematopoietic stem cell self-renewal and engraftment over serial transplants; p18-null HSCs resist exhaustion and maintain multilineage potential for >3 years of serial transfers, with effects shown to antagonize p21-driven senescence at the stem cell level. Serial bone marrow transplantation, competitive repopulation assay, flow cytometry, long-term culture Blood High 16234365
2006 MEN2A-specific RET(C634R) simultaneously represses p18/Ink4c and p27 mRNA levels while elevating cyclin D1, requiring functional MAPK signaling; RET2A-dependent p18 repression alone is sufficient to increase proliferation, and MEN2A adrenal tumors recapitulate this expression profile in vivo. Inducible RET2A expression, RT-PCR, Western blot, MEK inhibitor treatment, cyclin D1/p18/p27 quantification in primary tumors Oncogene Medium 16953232
2006 p18(Ink4c) and Pten constrain a positive regulatory loop: deletion of p18 (or CDK4 overexpression, or Rb inactivation) activates Akt/PKB, but this is recessive to PTEN reduction, indicating that CDK-dependent Rb pathway outputs feed back to the PI3K/Akt pathway. Double-mutant mouse models (p18-/-, Pten+/-), Western blot for phospho-Akt, tumor analysis, LOH at Pten locus Molecular and cellular biology Medium 16738322
2008 p18(Ink4c) protein stability is regulated by polyubiquitination at preferred lysines K46 and K112; binding to CDK4 or CDK6 (active or inactive) inhibits polyubiquitination and stabilizes p18, while cyclin D1 competes with p18 for CDK binding and accelerates p18 degradation. Substitution of multiple lysines triggers misfolding and accelerates degradation. In vitro ubiquitination assay, site-directed mutagenesis (lysine-to-arginine substitutions), co-expression with CDKs and cyclin D1, half-life measurement Cell cycle High 19029828
2008 Lentiviral reconstitution of p18(INK4c) at physiologic levels in p18-deficient GBM cells induces senescence-like G1 arrest, while p18-proficient GBM cells are unaffected, establishing p18 as a functional tumor suppressor whose loss drives CDK-mediated cell cycle progression in GBM. Lentiviral reconstitution, cell cycle analysis (flow cytometry), immunohistochemistry on primary GBM tumors Cancer research Medium 18381405
2008 NaBu-induced p18(INK4c) upregulation requires intact Sp1 binding sites in the p18 promoter; NaBu causes histone H3/H4 hyperacetylation at the endogenous p18 promoter and enhanced Sp1 binding in vivo, and overexpression of p18 alone induces G0/G1 arrest and partial erythroid differentiation in K562 cells. Promoter reporter assays with Sp1 cluster mutations, chromatin immunoprecipitation (ChIP), flow cytometry, overexpression Molecular and cellular biochemistry Medium 18642058
2009 GATA3 directly binds to and represses INK4C transcription; loss of p18(INK4c) in mice causes spontaneous ER-positive luminal mammary tumors, and GATA3-driven expansion of luminal progenitor cells is mechanistically linked to p18 repression. ChIP demonstrating GATA3 binding at INK4C locus, transgenic/knockout mouse models, gene expression analysis, luciferase reporter Cancer cell High 19411068
2010 RET2A signaling induces N-Myc via MAPK; N-Myc then binds an initiator consensus element in the p18(Ink4c) promoter to repress p18 transcription; loss of N-Myc induction prevents RET2A-mediated p18 repression and hyperproliferation. Promoter ChIP for N-Myc binding, siRNA/dominant-negative N-Myc, RT-PCR, promoter reporter assay, MEK inhibitor Molecular oncology Medium 21112821
2011 A reduced-expression NZB allele of Cdkn2c (due to an SNP in the promoter) causes defective G1 arrest in splenic B cells and increased proliferation of peritoneal B1a cells, mapping CDKN2C as the functional gene within the Sle2c1 lupus susceptibility locus responsible for B1a cell expansion. Genetic mapping, promoter SNP identification, B cell proliferation assay, cell cycle analysis, co-segregation analysis Journal of immunology Medium 21543644
2012 BRAF(V600E)/NRAS(G12D)-driven MAPK signaling promotes G1 melanoma cell proliferation through AP-1 (c-Jun)-mediated transcriptional repression of CDKN2C; dominant-negative AP-1 restores CDKN2C expression and pharmacological CDK2/4 inhibition augments effects of BRAF/MEK inhibitors in vitro and in vivo. Dominant-negative c-Jun expression, Western blot, flow cytometry, cell proliferation assay, xenograft tumor model Journal of the National Cancer Institute Medium 22997239
2013 Gata3 associates with Ruvbl2 and, as a complex, directly binds the Cdkn2c locus to repress its transcription in Th2 cells; Gata3-dependent repression of Cdkn2c facilitates Th2 cell proliferation, and knockdown of Cdkn2c rescues the proliferation defect in Gata3-deficient Th2 cells. Co-immunoprecipitation of Gata3/Ruvbl2 complex, ChIP at Cdkn2c locus, Ruvbl2 knockdown, Cdkn2c knockdown rescue experiment, airway inflammation model PNAS High 24167278
2013 p18(Ink4c) interacts with CDK4 in adult human pancreatic β-cells (detected by co-immunoprecipitation), and p18 protein localizes predominantly to the cytosol while p27(Kip1) localizes to nuclei, both contributing to maintenance of β-cell quiescence. Co-immunoprecipitation, immunofluorescence/confocal microscopy, subcellular fractionation, BrdU incorporation assay Islets Medium 23896637
2015 Small-molecule inhibitors of p18(INK4c) identified by in silico structure-based screening specifically block p18 activity and promote ex vivo expansion of functional murine and human hematopoietic stem cells; lead compound XIE18-6 analogue (compound 40) expands HSCs with ED50 = 5.21 nM without cytotoxicity. In silico 3D screening based on p18 structure, SAR synthesis, HSC expansion assay (long-term culture), single-cell analysis, competitive repopulation in mice Nature communications / Scientific reports Medium 25692908 26681454
2016 p18(INK4c) functions as a cell-intrinsic inhibitor of gammaherpesvirus reactivation from latency; the viral cyclin specifically bypasses p18 to enable reactivation, and genetic ablation of p18 alone is sufficient to render the viral cyclin dispensable for reactivation from latency. Knockout mouse genetics (p18-/-, p27-/- single and double knockouts), recombinant virus with p18 knock-in (p18KI), viral reactivation assay, BAFF cytokine treatment Journal of virology High 26292318 29298882
2016 p18(INK4c) and p57(Kip2) nuclear localization is associated with antiproliferative TKI activity in CML cells; TKI treatment reduces nuclear p18 in CML leukemic stem cells, suggesting that subcellular redistribution of p18 contributes to quiescence maintenance after TKI treatment. Subcellular fractionation, immunofluorescence, cell cycle analysis in CML cell lines and primary CD34+CD38-lin- LSCs and HSCs Cell cycle Low 26985855
2016 PML/RARα directly binds the CDKN2C promoter and represses its transcription in a dose-dependent manner; all-trans retinoic acid releases PML/RARα from chromatin and restores CDKN2C expression; ectopic CDKN2C expression induces G0/G1 arrest and partial differentiation in APL NB4 cells. Chromatin immunoprecipitation (ChIP-qPCR), luciferase reporter assay, ATRA treatment, CDKN2C overexpression, flow cytometry Frontiers of medicine Medium 27888400
2018 SETDB2 (a protein lysine methyltransferase) silences CDKN2C through histone H3K9 trimethylation at its locus; SETDB2 is a direct E2A-PBX1 target gene, establishing an oncogenic axis E2A-PBX1→SETDB2→H3K9me3 at CDKN2C→CDKN2C repression in pre-BCR+ ALL. ChIP for H3K9me3 at CDKN2C locus, SETDB2 knockdown, E2A-PBX1 ChIP, gene expression analysis, in vitro and in vivo leukemia maintenance assays Cell reports High 29694893
2020 CDKN2C induces G1 arrest by inhibiting CDK4/6, which is required for efficient HBV replication; CDKN2C is overexpressed in highly permissive hepatocytes and HBV-infected patients, and its loss reduces viral transcription enhancer activity, identifying CDKN2C-dependent G1 arrest as a proviral mechanism. Genome-wide gain-of-function screen, validation in primary human hepatocytes, gene knockdown/overexpression, viral replication assay, transcription enhancer reporter Nature communications Medium 32483149
2020 LINC00673 lncRNA represses CDKN2C expression through EZH2-mediated H3K27 trimethylation at the CDKN2C promoter; EZH2 inhibition or LINC00673 knockdown increases CDKN2C protein, and CDKN2C depletion restores G1/S progression in cells with reduced LINC00673. ChIP for H3K27me3 at CDKN2C promoter, EZH2 inhibitor treatment, siRNA knockdown, Western blot, flow cytometry Frontiers in oncology Medium 33014799
2022 p18INK4C protects CDK6 from degradation by the CDK6-specific PROTAC BSJ-03-123: CDK6 complexes containing p18INK4C (or p16INK4A) are shielded from PROTAC-mediated degradation; elevated INK4 levels in KMT2A-MLLT3+ AML cells correlate with resistance to CDK6 degradation. CDK6 degrader (PROTAC BSJ-03-123) treatment, Western blot, co-immunoprecipitation, proliferation assay in AML cell lines Cancers Medium 35326705
2023 CBX8 directly binds to the CDKN2C promoter and establishes H2AK119 ubiquitination to repress CDKN2C transcription in lung adenocarcinoma; CBX8 depletion reduces H2AK119ub enrichment at the CDKN2C promoter, and CDKN2C knockdown rescues the growth/invasion suppression caused by CBX8 depletion. ChIP assay for CBX8 binding and H2AK119ub at CDKN2C promoter, CBX8 knockdown/overexpression, CDKN2C knockdown rescue experiment, RNA sequencing Journal of cellular physiology Medium 37733753
2024 CDKN2C overexpression enhances radiosensitivity of osteosarcoma cells by inducing G1 arrest through suppression of CDK4 expression and Thr172 phosphorylation (but not CDK6 or Cyclin D1 expression), leading to reduced pRb Ser807/811 phosphorylation and increased apoptosis (BAX, Caspase-3) when combined with irradiation. Lentiviral CDKN2C overexpression, Western blot for CDK4 phosphorylation and pRb phosphorylation, flow cytometry cell cycle analysis, xenograft mouse model, apoptosis assay Biochemical and biophysical research communications Medium 39426133
2024 Oxidative modification of miR-30c at positions 4 and 5 (G→O8G, producing 4,5-oxo-miR-30c) causes mismatch recognition of CDKN2C mRNA, reducing CDKN2C protein levels and promoting cardiac fibroblast proliferation; unmodified miR-30c does not target CDKN2C in this manner. Luciferase reporter assay, miRNA immunoprecipitation with O8G antibody, cardiac fibrosis animal models (Ang II, ischemia-reperfusion), overexpression of oxidized miR-30c mimics Scientific reports Medium 38849466
2025 RNF149, a RING finger ubiquitin ligase, ubiquitinates CDKN2C protein in head and neck squamous cell carcinoma; RNF149 and CDKN2C show an inverse expression correlation in tissue arrays, and RNF149 knockdown reduces HNSC proliferation while altering CDK inhibitor sensitivity. Proximity ligation assay, immunoprecipitation, gene knockdown, proliferation/cell cycle assay, 3D assay, tissue array immunohistochemistry Anticancer research Low 42049330

Source papers

Stage 0 corpus · 90 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes & development 330 9744866
1999 Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. The Journal of biological chemistry 268 10358062
2000 Limited overlapping roles of P15(INK4b) and P18(INK4c) cell cycle inhibitors in proliferation and tumorigenesis. The EMBO journal 225 10880462
2001 Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. The American journal of pathology 219 11485924
2011 Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival. Clinical cancer research : an official journal of the American Association for Cancer Research 153 21994415
2010 The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clinical genetics 151 20507346
2001 Involvement of p21(WAF1/Cip1), p27(Kip1), and p18(INK4c) in troglitazone-induced cell-cycle arrest in human hepatoma cell lines. Hepatology (Baltimore, Md.) 148 11343236
1997 Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6. Immunity 133 9052836
2005 The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation. Genes & development 131 16260494
2005 Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood 102 16234365
2001 Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18(Ink4c) and p19(Ink4d). Molecular and cellular biology 94 11287627
2008 Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clinical cancer research : an official journal of the American Association for Cancer Research 88 18829482
2002 CDK inhibitor p18(INK4c) is required for the generation of functional plasma cells. Immunity 87 12196289
2001 A single nucleotide polymorphism in the 3'untranslated region of the CDKN2A gene is common in sporadic primary melanomas but mutations in the CDKN2B, CDKN2C, CDK4 and p53 genes are rare. International journal of cancer 84 11668523
2003 Haploinsufficiency of p18(INK4c) sensitizes mice to carcinogen-induced tumorigenesis. Molecular and cellular biology 83 12556487
2009 CDK inhibitor p18(INK4c) is a downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis. Cancer cell 81 19411068
1999 Identification of two distinct deleted regions on the short arm of chromosome 1 and rare mutation of the CDKN2C gene from 1p32 in oligodendroglial tumors. Journal of neuropathology and experimental neurology 75 10515227
2003 Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells. British journal of cancer 65 12698196
2000 Cooperation of p27(Kip1) and p18(INK4c) in progestin-mediated cell cycle arrest in T-47D breast cancer cells. Molecular and cellular biology 64 10713180
1996 Analysis of cyclin-dependent kinase inhibitor genes (CDKN2A, CDKN2B, and CDKN2C) in childhood rhabdomyosarcoma. Genes, chromosomes & cancer 63 8703847
2003 Hemangiosarcomas, medulloblastomas, and other tumors in Ink4c/p53-null mice. Cancer research 58 14500377
2010 In silico structural and functional analysis of fragments of the ankyrin repeat protein p18(INK4c). Journal of biomolecular structure & dynamics 49 19916573
1996 Molecular analysis of the cyclin-dependent kinase inhibitor family: p16(CDKN2/MTS1/INK4A), p18(INK4C) and p27(Kip1) genes in neuroblastomas. Cancer 45 8630967
2013 Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas. Hormones & cancer 44 23715670
2015 Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells. Nature communications 43 25692908
2009 Frequent loss of the CDKN2C (p18INK4c) gene product in pituitary adenomas. Genes, chromosomes & cancer 43 18973139
2008 Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme. Cancer research 42 18381405
2006 p18 Ink4c and Pten constrain a positive regulatory loop between cell growth and cell cycle control. Molecular and cellular biology 42 16738322
2001 An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation. Journal of immunology (Baltimore, Md. : 1950) 42 11544316
2016 Role of CDKN2C Copy Number in Sporadic Medullary Thyroid Carcinoma. Thyroid : official journal of the American Thyroid Association 40 27610696
2010 MEN-4 and other multiple endocrine neoplasias due to cyclin-dependent kinase inhibitors (p27(Kip1) and p18(INK4C)) mutations. Best practice & research. Clinical endocrinology & metabolism 39 20833334
2004 Reduced expression of cell cycle regulator p18(INK4C) in human hepatocellular carcinoma. Hepatology (Baltimore, Md.) 39 15349907
1999 Homozygous deletions of the CDKN2C/p18INK4C gene on the short arm of chromosome 1 in anaplastic oligodendrogliomas. Brain pathology (Zurich, Switzerland) 38 10517502
1998 Analysis of CDKN2A, CDKN2B, CDKN2C, and cyclin Ds gene status in hepatoblastoma. Hepatology (Baltimore, Md.) 38 9537438
1998 Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study. International journal of cancer 36 9724087
1999 Tumor suppressor INK4: comparisons of conformational properties between p16(INK4A) and p18(INK4C). Journal of molecular biology 35 10556039
2012 Dual suppression of the cyclin-dependent kinase inhibitors CDKN2C and CDKN1A in human melanoma. Journal of the National Cancer Institute 33 22997239
2018 SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression. Cell reports 29 29694893
1998 Structural and functional analysis of cyclin-dependent kinase inhibitor genes (CDKN2A, CDKN2B, and CDKN2C) in neuroblastoma. Pediatric research 29 9432125
2013 Gata3/Ruvbl2 complex regulates T helper 2 cell proliferation via repression of Cdkn2c expression. Proceedings of the National Academy of Sciences of the United States of America 28 24167278
2009 Expression of p18(INK4C) is down-regulated in human pituitary adenomas. Endocrine pathology 28 19401813
2020 miR-21-5p promotes cell proliferation and G1/S transition in melanoma by targeting CDKN2C. FEBS open bio 27 32090490
2011 Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1. Journal of immunology (Baltimore, Md. : 1950) 27 21543644
2006 Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis. Oncogene 25 16953232
2003 Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c. Oncogene 25 12821941
2013 Zebrafish dmrta2 regulates the expression of cdkn2c in spermatogenesis in the adult testis. Biology of reproduction 24 23175770
2007 Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression, and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumours. Clinical endocrinology 24 17803708
2006 Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression. Cell division 23 17049078
2003 p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver. Hepatology (Baltimore, Md.) 23 12668976
1995 Molecular analysis of a family of cyclin-dependent kinase inhibitor genes (p15/MTS2/INK4b and p18/INK4c) in non-small cell lung cancers. Molecular carcinogenesis 23 8519415
2012 Cyclin-dependent kinase inhibitor Cdkn2c deficiency promotes B1a cell expansion and autoimmunity in a mouse model of lupus. Journal of immunology (Baltimore, Md. : 1950) 22 22896639
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
2004 Activation of protein kinase C promotes human cancer cell growth through downregulation of p18(INK4c). Oncogene 20 15107819
2020 LINC00673 Represses CDKN2C and Promotes the Proliferation of Esophageal Squamous Cell Carcinoma Cells by EZH2-Mediated H3K27 Trimethylation. Frontiers in oncology 19 33014799
2015 Discovery of novel INK4C small-molecule inhibitors to promote human and murine hematopoietic stem cell ex vivo expansion. Scientific reports 19 26681454
2006 Hematopoietic stem cells are not the direct target of spontaneous leukemic transformation in p18(INK4C)-null reconstituted mice. Cancer research 19 16397248
2020 A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor. Nature communications 18 32483149
2008 Differential post-transcriptional regulation of two Ink4 proteins, p18 Ink4c and p19 Ink4d. Cell cycle (Georgetown, Tex.) 17 19029828
2007 Mutational analysis of p27 (CDKN1B) and p18 (CDKN2C) in sporadic pancreatic endocrine tumors argues against tumor-suppressor function. Neoplasia (New York, N.Y.) 16 17710155
2020 CDKN2C-Null Leiomyosarcoma: A Novel, Genomically Distinct Class of TP53/RB1-Wild-Type Tumor With Frequent CIC Genomic Alterations and 1p/19q-Codeletion. JCO precision oncology 14 33015533
2018 Interplay between p53 and Ink4c in spermatogenesis and fertility. Cell cycle (Georgetown, Tex.) 13 29334315
2017 Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors. Journal of endocrinological investigation 13 29134609
2002 Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation. The American journal of pathology 13 11891212
2022 CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML. Cancers 12 35326705
2013 The negative cell cycle regulators, p27(Kip1), p18(Ink4c), and GSK-3, play critical role in maintaining quiescence of adult human pancreatic β-cells and restrict their ability to proliferate. Islets 12 23896637
2008 Sodium butyrate-induced upregulation of p18( INK4C ) gene affects K562 cell G (0)/G (1) arrest and differentiation. Molecular and cellular biochemistry 12 18642058
2021 CDKN2C expression in adipose tissue is reduced in type II diabetes and central obesity: impact on adipocyte differentiation and lipid storage? Translational research : the journal of laboratory and clinical medicine 11 34896253
2012 Antitumor activity of cell-permeable p18(INK4c) with enhanced membrane and tissue penetration. Molecular therapy : the journal of the American Society of Gene Therapy 10 22617107
2023 CBX8 promotes lung adenocarcinoma growth and metastasis through transcriptional repression of CDKN2C and SCEL. Journal of cellular physiology 9 37733753
2019 Novel use of a Clinical Laboratory Improvements Amendments (CLIA)-certified Cyclin-Dependent Kinase N2C (CDKN2C) loss assay in sporadic medullary thyroid carcinoma. Surgery 9 31648931
2017 Role of CDKN2C Fluorescence In Situ Hybridization in the Management of Medullary Thyroid Carcinoma. Annals of clinical and laboratory science 9 29066476
2015 A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18(INK4c) To Promote Reactivation from Latency. Journal of virology 9 26292318
2024 Oxidative modification of miR-30c promotes cardiac fibroblast proliferation via CDKN2C mismatch. Scientific reports 8 38849466
2022 Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism. Journal of endocrinological investigation 8 36334246
2012 An opposite effect of the CDK inhibitor, p18(INK4c) on embryonic stem cells compared with tumor and adult stem cells. PloS one 8 23049777
2010 N-Myc is a downstream target of RET signaling and is required for transcriptional regulation of p18(Ink4c) by the transforming mutant RET(C634R). Molecular oncology 7 21112821
2018 Host Tumor Suppressor p18INK4c Functions as a Potent Cell-Intrinsic Inhibitor of Murine Gammaherpesvirus 68 Reactivation and Pathogenesis. Journal of virology 5 29298882
2013 The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T-cell-mediated pathology in B6.Fas(lpr) mice. Genes and immunity 5 23698709
2006 Ink4c is dispensable for tumor suppression in Myc-induced B-cell lymphomagenesis. Oncogene 5 17099725
2016 Repression of CDKN2C caused by PML/RARα binding promotes the proliferation and differentiation block in acute promyelocytic leukemia. Frontiers of medicine 4 27888400
2014 Deletion of p18(INK4c) aggravates cisplatin-induced acute kidney injury. International journal of molecular medicine 3 24714825
2016 A novel lymphoid progenitor cell population (LSK(low)) is restricted by p18(INK4c). Experimental hematology 2 27287689
2005 Lack of effect of extremely low frequency electromagnetic fields on cyclin-dependent kinase 4 inhibitor gene p18(INK4C) in electric energy workers. Archives of medical research 2 15847943
2025 A Case of CDKN2C/CIC Null Epithelioid Leiomyosarcoma With a Low-grade Component Indistinguishable From Leiomyoma. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 1 40340925
2025 A Genomic Alteration in GATA3 Affects Treatment Responses With a CDK4/6 Inhibitor Collaborating With p18INK4C Expression in Advanced Breast Carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 1 40680849
2024 Enhancing radiosensitivity in osteosarcoma via CDKN2C overexpression: A mechanism involving G1 phase arrest mediated by inhibition of CDK4 expression and Thr172 phosphorylation. Biochemical and biophysical research communications 1 39426133
2006 Long-term engraftment of p18(INK4C)-deficient hematopoietic stem cells is enhanced in the sublethally-irradiated recipients. Science in China. Series C, Life sciences 1 16989285
2003 The effects of inhibiting P18(INK4C) expression on the invasion of gastric adenocarcinoma cell line. Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica 1 12796810
2026 Ubiquitin Ligase RNF149 Promotes Head and Neck Cancer Growth via Downregulation of CDKN2C. Anticancer research 0 42049330
2025 Deletion of p18INK4c enhances both osteogenesis and hematopoietic supportive capacity of bone marrow mesenchymal stromal cells. Stem cell research & therapy 0 40597397

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