Affinage

CDKN2C

Cyclin-dependent kinase 4 inhibitor C · UniProt P42773

Length
168 aa
Mass
18.1 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKN2C/p18(INK4c) is a CDK inhibitor that restrains G1-phase cell cycle progression by forming binary complexes with CDK4 and especially CDK6, competitively displacing D-type cyclins to block pRb phosphorylation and enforce cell cycle exit during terminal differentiation in B cells, T cells, adipocytes, oligodendrocyte precursors, and spermatocytes (PMID:8001816, PMID:7739547, PMID:9052836, PMID:10358062). p18 functions as a haploinsufficient tumor suppressor whose loss cooperates with deficiency of p27(Kip1), p53, or Pten to drive pituitary, thyroid, mammary, and hematopoietic tumors in mice, and whose expression is transcriptionally repressed by GATA3/RuvBL2, AP-1 downstream of BRAF(V600E)/MAPK signaling, and epigenetically silenced by SETDB2-mediated H3K9me3 and PRMT6-mediated H3R2me2a (PMID:9744866, PMID:12556487, PMID:19411068, PMID:29694893, PMID:32945431). In the hematopoietic stem cell compartment, p18 restricts self-renewal such that its genetic or pharmacological inhibition expands functional HSCs (PMID:16234365, PMID:25692908). Somatic loss-of-function mutations in CDKN2C occur in RET-associated medullary thyroid carcinoma and pheochromocytoma, and CDKN2C silencing contributes to glioblastoma and melanoma progression (PMID:18942719, PMID:18381405, PMID:22997239).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1994 High

    Identification of p18(INK4c) as a CDK6/CDK4-specific inhibitor that forms binary (not ternary) complexes and suppresses growth in a pRb-dependent manner established the founding biochemical mechanism of this INK4 family member.

    Evidence Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assays, and ectopic expression growth suppression in human cells

    PMID:8001816

    Open questions at the time
    • Structural basis for CDK6 preference over CDK4 not resolved
    • Endogenous physiological context of p18 action unknown
  2. 1995 High

    Demonstration that p18 specifically inhibits CDK4/6 but not CDK2 or CDC2, and displaces cyclins from preformed complexes in vivo, clarified the competitive displacement mechanism and CDK selectivity of INK4c.

    Evidence In vitro kinase assays across multiple CDK-cyclin pairs, co-immunoprecipitation of endogenous complexes, FACS cell cycle analysis in mouse cells

    PMID:7739547 PMID:8663131

    Open questions at the time
    • Quantitative binding affinities for CDK4 vs CDK6 not determined
    • Whether cyclin displacement is kinetically reversible in vivo unknown
  3. 1997 High

    Discovery that IL-6 induces p18 during B cell terminal differentiation, coupling CDK6 inhibition to cell cycle exit and immunoglobulin secretion, provided the first physiological differentiation context for p18.

    Evidence Co-immunoprecipitation showing enhanced p18-CDK6 association, overexpression reconstituting coupled differentiation and arrest in lymphoblastoid cells

    PMID:9052836

    Open questions at the time
    • Transcriptional vs post-transcriptional regulation by IL-6 not dissected
    • Whether p18 is required (vs sufficient) for plasma cell differentiation not tested
  4. 1998 High

    Knockout mouse studies established p18 as a bona fide tumor suppressor whose loss causes pituitary hyperplasia/adenoma and cooperates with p27 loss through independent pathways converging on Rb, defining the in vivo tumor suppressor function.

    Evidence Gene targeting in mice with single and double (p18/p27) knockouts, histopathology, epistasis analysis

    PMID:9744866

    Open questions at the time
    • Cell-autonomous vs systemic (e.g. hormonal) contribution to pituitary tumorigenesis not separated
    • Human pituitary tumor relevance not established
  5. 1999 High

    NMR structural analysis revealed that p18 has greater kinetic stability than p16 and p15, with the fourth ankyrin repeat as the stability core, providing a biophysical basis for differential INK4 family behavior.

    Evidence NMR heteronuclear NOE and H/D exchange measurements, chemical denaturation comparison

    PMID:10556039

    Open questions at the time
    • No co-crystal structure with CDK6 to map the binding interface
    • Functional consequence of enhanced stability not tested in cells
  6. 1999 High

    Identification of PPARγ as a direct transcriptional activator of p18 during adipogenesis linked p18 induction to the irreversible cell cycle exit accompanying terminal differentiation in a non-hematopoietic lineage.

    Evidence Ectopic PPARγ expression in fibroblasts with ligand-dependent p18 mRNA/protein induction

    PMID:10358062

    Open questions at the time
    • Direct promoter binding by PPARγ not shown by ChIP
    • Whether p18 is necessary for adipocyte cell cycle exit not tested by loss-of-function
  7. 2000 High

    Studies in breast cancer cells showed that progestin-induced p18 upregulation reassorts CDK-cyclin-inhibitor complexes to indirectly suppress cyclin E-CDK2 activity through cooperation with p27, revealing a two-step CDK inhibition cascade linking INK4 and Cip/Kip families.

    Evidence Co-immunoprecipitation, in vitro reconstitution with recombinant p18, gel filtration of endogenous complexes

    PMID:10713180

    Open questions at the time
    • Stoichiometric requirements for complex reassortment not quantified
    • In vivo relevance of progestin-p18 axis in mammary tumor suppression not tested
  8. 2001 High

    Functional studies in knockout mice extended p18's differentiation roles to T cells (CDK6-selective threshold on TCR proliferation), B cell plasma cell differentiation (required for antibody production), and spermatogenesis (cooperation with p19/INK4d for meiotic progression), demonstrating broad lineage-specific functions.

    Evidence Single and double knockout mice with immunization, proliferation assays, histopathology, and hormone measurements

    PMID:11287627 PMID:11544316 PMID:12196289

    Open questions at the time
    • Whether CDK6 selectivity in T cells reflects expression patterns or intrinsic affinity not resolved
    • Molecular mechanism linking p18 loss to meiotic defects unknown
  9. 2003 High

    Demonstration that p18 is haploinsufficient for tumor suppression — heterozygous mice develop carcinogen-induced tumors without loss or silencing of the remaining allele — established a dosage-sensitive mode of tumor suppression distinct from classical two-hit models.

    Evidence Chemical carcinogenesis in p18+/- mice with LOH analysis and sequencing of remaining allele

    PMID:12556487

    Open questions at the time
    • Whether haploinsufficiency operates in human cancers not tested
    • Threshold level of p18 protein required for tumor suppression unknown
  10. 2005 High

    Discovery that p18 restricts hematopoietic stem cell self-renewal, with p18 loss improving long-term engraftment and opposing the exhaustion phenotype of p21 deficiency, positioned p18 as a stem cell quiescence regulator distinct from proliferation arrest.

    Evidence Serial competitive bone marrow transplantation in single and double knockout mice

    PMID:16234365

    Open questions at the time
    • Whether p18 acts cell-autonomously in HSCs vs through niche effects not fully resolved
    • CDK4 vs CDK6 target in HSCs not determined
  11. 2006 Medium

    Genetic epistasis between p18/Pten and p18/p27 in thyroid and pituitary tumorigenesis revealed crosstalk between CDK4-Rb and PI3K/Akt/mTOR pathways, with p18 deletion activating Akt, suggesting a feedback loop from cell cycle control to growth signaling.

    Evidence Compound mutant mice, Western blot for Akt phosphorylation, tumor incidence and histopathology

    PMID:16738322 PMID:16953232

    Open questions at the time
    • Mechanism of CDK4-Rb to Akt feedback not molecularly defined
    • Whether feedback operates in human tumors unknown
  12. 2009 High

    ChIP and reporter assays showed GATA3 directly binds and represses the CDKN2C promoter in mammary and Th2 cells (via a RuvBL2-containing complex), and p18-null mice develop ER-positive luminal tumors, establishing a GATA3→p18 transcriptional axis controlling luminal progenitor expansion.

    Evidence ChIP, luciferase reporter, co-immunoprecipitation of GATA3-RuvBL2, knockout mice with tumor histopathology, siRNA rescue

    PMID:19411068 PMID:24167278

    Open questions at the time
    • Whether GATA3 mutations in human breast cancer act through p18 derepression not tested
    • Genomic occupancy of GATA3-RuvBL2 at CDKN2C not mapped at nucleotide resolution
  13. 2012 Medium

    Identification of AP-1-mediated CDKN2C transcriptional repression downstream of BRAF(V600E)/MAPK signaling in melanoma explained how oncogenic MAPK activity overrides the p18-CDK4/6-Rb checkpoint.

    Evidence Dominant-negative AP-1 derepresses CDKN2C, CDK4 inhibitor blocks BRAF(V600E) proliferative effects in vitro and xenograft

    PMID:22997239

    Open questions at the time
    • Direct AP-1 binding to CDKN2C promoter not confirmed by ChIP
    • Relative contribution of p18 vs p16 repression in melanoma not quantified
  14. 2015 Medium

    Structure-based small-molecule inhibitors of p18 expanded functional HSCs in culture and transplantation, providing pharmacological proof-of-concept that p18's CDK-inhibitory activity can be therapeutically targeted to enhance stem cell self-renewal.

    Evidence In silico screening against p18 structure, in vitro kinase assay, single-cell HSC culture, transplantation

    PMID:25692908

    Open questions at the time
    • Selectivity of inhibitors for p18 over other INK4 members not fully characterized
    • Long-term safety of p18 inhibition in vivo not assessed
  15. 2018 High

    Discovery that SETDB2 deposits H3K9me3 at the CDKN2C locus downstream of the E2A-PBX1 oncofusion to silence p18 in pre-B ALL established an epigenetic silencing axis as a tumor maintenance mechanism.

    Evidence ChIP for H3K9me3, SETDB2 knockdown restoring CDKN2C expression, in vivo leukemia maintenance assay

    PMID:29694893

    Open questions at the time
    • Whether H3K9me3-based silencing is reversible with epigenetic drugs not tested
    • Other SETDB2 targets that may contribute to leukemia maintenance not excluded
  16. 2020 Medium

    Identification of miR-21-5p and PRMT6 (H3R2me2a) as additional negative regulators of CDKN2C in melanoma and lung adenocarcinoma, respectively, expanded the repertoire of post-transcriptional and epigenetic mechanisms that silence p18 in cancer.

    Evidence Luciferase 3'UTR reporter for miR-21-5p, ChIP for H3R2me2a at p18 promoter with PRMT6 knockdown, xenograft validation

    PMID:32090490 PMID:32945431

    Open questions at the time
    • Relative quantitative contribution of each silencing mechanism in individual tumors unknown
    • Whether PRMT6 and SETDB2 act on the same or distinct chromatin states at CDKN2C not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structural basis for p18's strong CDK6 preference over CDK4, whether the CDK4-Rb-to-Akt feedback loop is a general mechanism in human cancers, and the therapeutic window for pharmacological p18 inhibition in stem cell expansion without tumor risk.
  • No co-crystal structure of p18-CDK6 complex available
  • Mechanism of CDK4-Rb to Akt feedback not molecularly defined
  • Long-term oncogenic risk of p18 inhibition in HSC expansion not assessed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 4 R-HSA-162582 Signal Transduction 3
Partners
CDK4CDK6GATA3PRMT6RUVBL2SETDB2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 CDKN2C/p18(INK4c) directly binds CDK6 (strongly) and CDK4 (weakly) in vivo and in vitro, forms binary complexes (not ternary with cyclins), inhibits cyclin D-CDK6 kinase activity, and suppresses cell growth in a pRb-dependent manner. Yeast two-hybrid screen, co-immunoprecipitation, in vitro kinase assay, ectopic expression with growth suppression assay Genes & development High 8001816
1995 Mouse p18(INK4c) specifically inhibits CDK4 and CDK6 kinase activities but not cyclin E-CDK2, cyclin A-CDK2, or cyclin B-CDC2; it binds CDK4/6 whether free or in cyclin D complexes, displaces cyclins from CDKs in vivo (forming binary inhibitor-CDK complexes), and ectopic expression causes G1 arrest. In vitro kinase assays, co-immunoprecipitation, ectopic expression with FACS cell cycle analysis Molecular and cellular biology High 7739547
1997 In terminally differentiating B cells, IL-6 activates p18(INK4c) expression, markedly enhances its association with CDK6, suppresses pRb phosphorylation, and causes cell cycle arrest; overexpression of p18 in IgM-bearing lymphoblastoid cells reconstitutes coupled differentiation and cell cycle arrest. Co-immunoprecipitation, Western blot, ectopic overexpression, flow cytometry Immunity High 9052836
1998 p18(INK4c)-deficient mice develop gigantism, organomegaly, pituitary hyperplasia progressing to adenoma; combined loss of p18 and p27 (two distinct CDK inhibitor pathways) leads to invariable pituitary adenoma death by 3 months, demonstrating that p18 and p27 suppress pituitary tumorigenesis via separate pathways converging on Rb. Gene targeting (knockout mice), histopathology, epistasis with p27 double knockout Genes & development High 9744866
1999 NMR and H/D exchange analyses show that p18(INK4c) is more kinetically stable than p16(INK4A) and p15(INK4B), with slowly exchanging residues concentrated in the fourth ankyrin repeat, conferring distinct conformational flexibility on the microsecond–hour timescale. NMR (heteronuclear NOE, H/D exchange), chemical denaturation Journal of molecular biology High 10556039
1999 During adipogenesis, PPARγ directly induces p18(INK4c) expression at the onset of terminal differentiation, coordinating irreversible G1 arrest; ectopic PPARγ in non-precursor fibroblasts induces p18 mRNA and protein in a ligand-dependent manner. Stable cell lines with ectopic PPARγ, Western blot, Northern blot, PPARγ ligand treatment The Journal of biological chemistry High 10358062
2000 Ablation of p18(INK4c) alone or combined with p15(INK4b) causes lymphoproliferative disorders and renal/mammary epithelial cysts in mice; p15 but not p18 loss confers proliferative advantage to MEFs and sensitizes them to H-ras transformation, indicating non-redundant tumor suppressor roles in different lineages. Gene targeting (single and double knockout mice), MEF transformation assays, histopathology The EMBO journal High 10880462
2000 Progestin treatment of T-47D breast cancer cells increases p18(INK4c) expression and promotes its extensive association with CDK4 and CDK6; recombinant p18(INK4c) in vitro reassorts cyclin-CDK-inhibitor complexes, indirectly reducing cyclin E-CDK2 activity, demonstrating cooperation with p27(Kip1) in G1 arrest. Co-immunoprecipitation, in vitro kinase assay with recombinant p18, Western blot, gel filtration Molecular and cellular biology High 10713180
2001 p18(INK4c) is required for B cell terminal differentiation into functional plasma cells: p18-null B cells hyperproliferate in germinal centers and extrafollicular foci but produce severely reduced antibody titers, linking p18-mediated CDK6 inhibition to cell cycle exit required for plasma cell function. Knockout mice, B cell immunization assays, antibody titer measurement, histology Immunity High 12196289
2001 p18(INK4c) selectively associates with and inhibits CDK6 (not CDK4) in activated T cells; p18-null T cells hyperproliferate in response to CD3 stimulation, and p18 sets an inhibitory threshold on TCR-mediated proliferation via CDK6. Knockout mice, co-immunoprecipitation, T cell proliferation assays, flow cytometry Journal of immunology High 11544316
2001 Combined loss of Ink4c and Ink4d in mice causes male infertility through delayed spermatogonial exit from mitosis, aberrant meiosis, spermatocyte apoptosis, and Leydig cell hyperplasia with reduced testosterone; Ink4c single loss causes Leydig cell hyperplasia independently of Ink4d. Single and double knockout mice, histopathology, hormone measurements, cell cycle analysis Molecular and cellular biology High 11287627
2002 p18(INK4c) is overexpressed in multiple myeloma (MM) cell lines with p16 co-deletion; zinc-inducible ectopic p18 expression in p18-deficient MM cells causes 40–45% growth suppression and induces apoptosis, demonstrating that p18 inhibits the cyclin D1/CDK/pRb pathway in myeloma. Inducible expression system, trypan blue exclusion, MTS assay, apoptosis assay Leukemia Medium 11840272
2002 Posttranscriptional upregulation of p18(INK4c) protein during oligodendrocyte precursor cell (OPC) proliferation contributes to a cell-intrinsic differentiation timer; overexpression of p18 in OPCs accelerates premature differentiation. Overexpression in primary OPC cultures, cell cycle analysis, differentiation assay Developmental biology Medium 11969268
2003 Haploinsufficiency of p18(INK4c) in mice sensitizes to carcinogen-induced tumorigenesis; the remaining wild-type allele is neither mutated nor silenced in heterozygote tumors, establishing p18 as a haploinsufficient tumor suppressor. Chemical carcinogenesis in p18+/- and p18-/- mice, LOH analysis, sequencing Molecular and cellular biology High 12556487
2005 Ink4c (p18) collaborates with p53 independently of Patched to suppress medulloblastoma: Ink4c haploinsufficiency combined with Ptc1 heterozygosity causes rapid medulloblastoma with loss of the wild-type Ptc1 allele (not Ink4c), showing Ink4c haploinsufficiency for tumor suppression in this context. Mouse genetics (compound heterozygous/null crosses), LOH analysis, GNP cell proliferation assays, in situ hybridization Genes & development High 16260494
2005 Deletion of p18(INK4c) in hematopoietic stem cells (HSCs) results in improved long-term engraftment and increased self-renewing divisions; p18 absence significantly decelerates hematopoietic exhaustion caused by p21 deficiency, demonstrating opposing roles of p18 (restricts self-renewal) and p21 (limits exhaustion) at the HSC level. Serial bone marrow transplantation, single KO and double KO mice, competitive repopulation assays Blood High 16234365
2006 p18(INK4c) cooperates with p27(Kip1) to suppress MEN-like pituitary and thyroid tumorigenesis; oncogenic RET2A represses p18 mRNA levels via MAPK signaling, reduces p18 protein, elevates cyclin D1, increases CDK activity and pRb phosphorylation, and p18 downregulation is required and sufficient for RET2A-mediated mitogenesis. Inducible RET2A expression, RT-PCR, Western blot, kinase assay, antisense knockdown, double KO mice Oncogene High 16953232
2006 p18 Ink4c and Pten cooperate to suppress tumorigenesis via a positive feedback loop between cell growth (PI3K/Akt/mTOR) and cell cycle control; p18 deletion, CDK4 overexpression, or viral Rb inactivation each cause Akt activation, suggesting the CDK4-Rb pathway feeds back to regulate Akt. Double mutant mice (p18/Pten), Western blot for Akt activation, tumor incidence analysis Molecular and cellular biology Medium 16738322
2008 Crystal structure of AIMP3/p18 (a component of the multi-tRNA synthetase complex, also known as p18 tumor suppressor) determined at 2.0 Å; structure reveals two distinct domains; mutations at the C-terminal domain abolish interaction with ATM and p53 activation, identifying residues critical for tumor-suppressive activity. X-ray crystallography, mutagenesis, co-immunoprecipitation, p53 activation assay The Journal of biological chemistry High 18343821
2008 Somatic mutations in CDKN2C/p18(INK4c) found in human RET-associated medullary thyroid carcinoma and pheochromocytoma cause amino acid substitutions in the CDK-interacting region, partially inhibit p18 function and reduce its stability, implicating p18 as a tumor suppressor in these cancers. Mutation sequencing of patient tumors, in vitro functional assays of mutant p18 International journal of cancer Medium 18942719
2008 Lentiviral reconstitution of p18(INK4c) expression at physiological levels in p18-deficient GBM cells induces senescence-like G1 arrest; p18-proficient GBM cells are unaffected, identifying p18 loss as a driver of CDK dysregulation in glioblastoma. Lentiviral gene reconstitution, flow cytometry (cell cycle), immunohistochemistry Cancer research Medium 18381405
2009 GATA3 directly binds the INK4C/CDKN2C promoter and represses its transcription, placing p18(INK4c) downstream of GATA3 in luminal mammary progenitor cells; p18-null mice spontaneously develop ER-positive luminal tumors with expanded luminal progenitor populations. ChIP, luciferase reporter assay, knockout mice, tumor histopathology, gene expression profiling Cancer cell High 19411068
2010 AIMP3/p18 overexpression causes proteasome-dependent degradation of mature lamin A (not lamin C, prelamin A, or progerin), leading to altered lamin A isoform stoichiometry, accelerated cellular senescence, nuclear morphology defects, and a progeroid phenotype in transgenic mice. Transgenic mice, Western blot, proteasome inhibitor treatment, cell morphology assay Aging cell Medium 20726853
2011 Cdkn2c/p18 deficiency in C57BL/6 mice causes dose-dependent expansion of peritoneal B1a cells (but not splenic conventional B cells) with enhanced homeostatic B1a proliferation; elevated B1a numbers are normalized by cyclin D2 deficiency, placing p18 upstream of cyclin D2 in B1a cell pool regulation. Knockout mice, flow cytometry, cyclin D2 double KO epistasis, autoantibody measurement Journal of immunology High 22896639
2012 MAPK/BRAF(V600E) signaling promotes melanoma G1 cell cycle progression via AP-1-mediated transcriptional repression of CDKN2C; dominant-negative AP-1 de-represses CDKN2C, and CDK4 inhibition antagonizes BRAF(V600E) proliferative effects. Dominant-negative AP-1, cell proliferation assay, Western blot, flow cytometry, in vivo xenograft Journal of the National Cancer Institute Medium 22997239
2013 GATA3 associates with RuvBL2 (Ruvbl2) to form a complex that directly binds the Cdkn2c locus and represses Cdkn2c expression in Th2 cells; knockdown of Cdkn2c rescues the proliferation defect of Gata3-deficient Th2 cells, establishing Cdkn2c as a key mediator of Gata3-driven Th2 cell proliferation. ChIP, co-immunoprecipitation, siRNA knockdown, in vitro proliferation assay, in vivo airway inflammation model Proceedings of the National Academy of Sciences of the United States of America High 24167278
2015 Small-molecule inhibitors identified by structure-based in silico screening against p18(INK4c) specifically block p18 activity and expand functional HSCs in short-term culture, demonstrating that pharmacological inhibition of p18's CDK-inhibitory function promotes HSC self-renewing division. In silico screening based on p18 protein structure, in vitro kinase inhibition assay, single-cell HSC culture, transplantation assay Nature communications Medium 25692908
2018 SETDB2 (protein lysine methyltransferase) suppresses CDKN2C expression via histone H3K9 tri-methylation at the CDKN2C locus downstream of the E2A-PBX1 chimeric transcription factor in pre-BCR+ ALL, establishing an oncogenic pathway that silences CDKN2C as a major tumor suppressor. ChIP, SETDB2 knockdown, gene expression analysis, in vitro and in vivo leukemia maintenance assays Cell reports High 29694893
2020 miR-21-5p directly targets CDKN2C 3'UTR (validated by luciferase reporter assay), decreases CDKN2C protein levels, and promotes G1/S transition and proliferation in melanoma cells; CDKN2C overexpression partially reverses miR-21-5p-driven proliferation. Luciferase reporter assay, miRNA mimic/inhibitor, Western blot, flow cytometry, rescue experiment FEBS open bio Medium 32090490
2020 PRMT6 epigenetically suppresses CDKN2C/p18 expression via asymmetric dimethylation of histone H3R2 at the p18 promoter; PRMT6 knockdown reduces H3R2me2a enrichment at the p18 promoter, activates p18 expression, induces G1/S arrest, and inhibits lung adenocarcinoma cell proliferation in vitro and in vivo. ChIP assay, PRMT6 siRNA knockdown, Western blot, cell cycle analysis, xenograft model Molecular medicine reports Medium 32945431
1996 p18(INK4c) and p16(INK4A) each form 1:1 binary complexes with CDK4/CDK6 (no free kinase detectable); p16 can dissociate preformed CDK4-cyclin D1 complexes in vitro, demonstrating competitive displacement of cyclin by INK4 inhibitors. In vitro dissociation assay with purified proteins, co-immunoprecipitation, Western blot The Journal of biological chemistry High 8663131
2014 miR-543 and miR-590-3p directly bind AIMP3/p18 transcripts and decrease AIMP3/p18 expression; their levels decline under senescence-inducing conditions in human MSCs, allowing AIMP3/p18 upregulation which induces senescence phenotypes including impaired clonogenicity and adipogenic differentiation. miRNA mimic/inhibitor transfection, luciferase reporter assay (direct binding), Western blot, senescence assays Age (Dordrecht, Netherlands) Medium 25465621

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes & development 765 8001816
1995 Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Molecular and cellular biology 618 7739547
1998 Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia 350 9639410
1998 CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes & development 330 9744866
2012 Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. The Journal of biological chemistry 304 22685290
1995 Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. Cancer research 271 7882351
2009 The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. The EMBO journal 270 19177150
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
1995 Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood. Blood 171 7606004
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 152 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 150 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 132 9052836
2005 The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation. Genes & development 130 16260494
2005 The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Cell 121 15680327
2003 Cleavage of Bax to p18 Bax accelerates stress-induced apoptosis, and a cathepsin-like protease may rapidly degrade p18 Bax. Blood 104 12816867
2005 Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood 102 16234365
1994 Regulation of phosphoprotein p18 in leukemic cells. Cell cycle regulated phosphorylation by p34cdc2 kinase. The Journal of biological chemistry 100 8144611
2006 Single-assay combination of Epstein-Barr Virus (EBV) EBNA1- and viral capsid antigen-p18-derived synthetic peptides for measuring anti-EBV immunoglobulin G (IgG) and IgA antibody levels in sera from nasopharyngeal carcinoma patients: options for field screening. Journal of clinical microbiology 96 16597877
2001 Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18(Ink4c) and p19(Ink4d). Molecular and cellular biology 94 11287627
1996 Alterations of the p15, p16,and p18 genes in osteosarcoma. Cancer genetics and cytogenetics 92 8603340
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
2001 Antibacterial, antitumor and hemolytic activities of alpha-helical antibiotic peptide, P18 and its analogs. The journal of peptide research : official journal of the American Peptide Society 87 12005420
2002 CDK inhibitor p18(INK4c) is required for the generation of functional plasma cells. Immunity 86 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
1996 The p18 component of the multisynthetase complex shares a protein motif with the beta and gamma subunits of eukaryotic elongation factor 1. FEBS letters 71 8849690
1996 Antisense RNA inhibition of phosphoprotein p18 expression abrogates the transformed phenotype of leukemic cells. Cancer research 65 8640838
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 64 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
2002 Posttranscriptional regulation of p18 and p27 Cdk inhibitor proteins and the timing of oligodendrocyte differentiation. Developmental biology 63 11969268
1996 Analysis of cyclin-dependent kinase inhibitor genes (CDKN2A, CDKN2B, and CDKN2C) in childhood rhabdomyosarcoma. Genes, chromosomes & cancer 63 8703847
1998 The crystal structure of H-2Dd MHC class I complexed with the HIV-1-derived peptide P18-I10 at 2.4 A resolution: implications for T cell and NK cell recognition. Immunity 62 9729040
1990 Amino acid sequence and characterization of a heparin-binding neurite-promoting factor (p18) from bovine brain. The Journal of biological chemistry 62 2229039
2003 Hemangiosarcomas, medulloblastomas, and other tumors in Ink4c/p53-null mice. Cancer research 58 14500377
2014 miR-543 and miR-590-3p regulate human mesenchymal stem cell aging via direct targeting of AIMP3/p18. Age (Dordrecht, Netherlands) 53 25465621
1996 Intragenic mutations of the p16(INK4), p15(INK4B) and p18 genes in primary non-small-cell lung cancers. International journal of cancer 53 8631583
2006 Characterization of the Babesia gibsoni P18 as a homologue of thrombospondin related adhesive protein. Molecular and biochemical parasitology 52 16675041
2018 UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity. eLife 50 30020076
2010 In silico structural and functional analysis of fragments of the ankyrin repeat protein p18(INK4c). Journal of biomolecular structure & dynamics 49 19916573
2009 P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development. International journal of cancer 48 18942719
2002 Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis. Leukemia 48 11840272
1996 Biochemical characterization of p16INK4- and p18-containing complexes in human cell lines. The Journal of biological chemistry 47 8663131
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