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Gene Review

CDKN2C  -  cyclin-dependent kinase inhibitor 2C (p18,...

Homo sapiens

Synonyms: CDKN6, Cyclin-dependent kinase 4 inhibitor C, Cyclin-dependent kinase 6 inhibitor, INK4C, p18, ...
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Disease relevance of CDKN2C


High impact information on CDKN2C

  • Methylation of INK4C (CDKN2C) was observed in four of 23 human MBs, and p18(INK4C) protein expression was extinguished in 14 of 73 cases [6].
  • Ectopic expression of p18 or p16 suppresses cell growth with a correlated dependence on endogenous wild-type pRb [7].
  • Thus, CDK inhibitors, in particular p18, are likely to play a pivotal role in controlling cell cycle arrest and cell death in terminal differentiation of late-stage B cells to plasma cells via inhibition of pRb phosphorylation by CDK6 [8].
  • Overexpression of p18 in IgM-bearing lymphoblastoid cells, which differentiated in response to IL-6 but did not exit the cell cycle, reconstituted coupled differentiation and cell cycle arrest [8].
  • Compared with their corresponding single mutant littermates, the p18(-)(/)(-); Men1(+/)(-) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas [9].

Chemical compound and disease context of CDKN2C


Biological context of CDKN2C


Anatomical context of CDKN2C


Associations of CDKN2C with chemical compounds


Physical interactions of CDKN2C

  • Gel shift analyses using p18 promoter-derived probes led to the identification of several multiprotein complexes that were found to contain different combinations of E2F proteins and/or Sp1 [20].
  • This mutation abrogates the ability of p18 to interact with CDK6 and renders p18 deficient in suppressing cell growth in a colony formation assay [10].
  • The paradigm of p18 suggests that transmembrane complexes formed by the nuclear lamins and LBR provide potential docking sites for integral membrane proteins of the nuclear envelope that equilibrate between the rough endoplasmic reticulum and the inner nuclear membrane [16].

Enzymatic interactions of CDKN2C

  • In all cell lines exposed to As(2)O(3), p21 Bax was proteolytically cleaved in a calpain-dependent way into the more proapoptotic p18 Bax, which was detected exclusively in a mitochondria-enriched subcellular fraction [21].

Regulatory relationships of CDKN2C

  • We and others found that overexpressed E2F proteins up-regulate p18 expression [20].

Other interactions of CDKN2C

  • Here we analyze the imprinting status of three additional CKIs, the abnormal expression and/or chromosomal localization of which has been implicated in human malignancy: CDKN1A, CDKN1B, and CDKN2C [22].
  • Indeed, p16INK4A and p15INK4B (products of expression of CDKN2A and CDKN2B respectively) were not observable while pl8INK4C (which is codified by CDKN2C) was clearly detectable in the samples analyzed [1].
  • We report the first detailed structure-function analyses of p18INK4C (p18), which is a homologue of the important tumor suppressor p16INK4A (p16) [23].
  • The present investigation reports the results of screening the 100 Swedish melanoma families for germline mutations in the CDK4, CDKN2C and TP53 genes [3].
  • Mutational inactivation of these elements revealed that the Sp1 sites were important for the basal activity of the promoter but could also mediate the effects of E2F1 on the p18 promoter [20].

Analytical, diagnostic and therapeutic context of CDKN2C


  1. Analysis of CDKN2A, CDKN2B, CDKN2C, and cyclin Ds gene status in hepatoblastoma. Iolascon, A., Giordani, L., Moretti, A., Basso, G., Borriello, A., Della Ragione, F. Hepatology (1998) [Pubmed]
  2. Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. Boström, J., Meyer-Puttlitz, B., Wolter, M., Blaschke, B., Weber, R.G., Lichter, P., Ichimura, K., Collins, V.P., Reifenberger, G. Am. J. Pathol. (2001) [Pubmed]
  3. Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study. Platz, A., Hansson, J., Ringborg, U. Int. J. Cancer (1998) [Pubmed]
  4. Analysis of cyclin-dependent kinase inhibitor genes (CDKN2A, CDKN2B, and CDKN2C) in childhood rhabdomyosarcoma. Iolascon, A., Faienza, M.F., Coppola, B., Rosolen, A., Basso, G., Della Ragione, F., Schettini, F. Genes Chromosomes Cancer (1996) [Pubmed]
  5. 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. Kulkarni, M.S., Daggett, J.L., Bender, T.P., Kuehl, W.M., Bergsagel, P.L., Williams, M.E. Leukemia (2002) [Pubmed]
  6. The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation. Uziel, T., Zindy, F., Xie, S., Lee, Y., Forget, A., Magdaleno, S., Rehg, J.E., Calabrese, C., Solecki, D., Eberhart, C.G., Sherr, S.E., Plimmer, S., Clifford, S.C., Hatten, M.E., McKinnon, P.J., Gilbertson, R.J., Curran, T., Sherr, C.J., Roussel, M.F. Genes Dev. (2005) [Pubmed]
  7. Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Guan, K.L., Jenkins, C.W., Li, Y., Nichols, M.A., Wu, X., O'Keefe, C.L., Matera, A.G., Xiong, Y. Genes Dev. (1994) [Pubmed]
  8. Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6. Morse, L., Chen, D., Franklin, D., Xiong, Y., Chen-Kiang, S. Immunity (1997) [Pubmed]
  9. p18Ink4c, but Not p27Kip1, Collaborates with Men1 To Suppress Neuroendocrine Organ Tumors. Bai, F., Pei, X.H., Nishikawa, T., Smith, M.D., Xiong, Y. Mol. Cell. Biol. (2007) [Pubmed]
  10. A p18 mutant defective in CDK6 binding in human breast cancer cells. Lapointe, J., Lachance, Y., Labrie, Y., Labrie, C. Cancer Res. (1996) [Pubmed]
  11. Molecular analysis of the cyclin-dependent kinase inhibitor genes p15INK4b/MTS2, p16INK4/MTS1, p18 and p19 in human cancer cell lines. Gemma, A., Takenoshita, S., Hagiwara, K., Okamoto, A., Spillare, E.A., McMemamin, M.G., Hussain, S.P., Forrester, K., Zariwala, M., Xiong, Y., Harris, C.C. Int. J. Cancer (1996) [Pubmed]
  12. Homozygous deletions of the CDKN2C/p18INK4C gene on the short arm of chromosome 1 in anaplastic oligodendrogliomas. Pohl, U., Cairncross, J.G., Louis, D.N. Brain Pathol. (1999) [Pubmed]
  13. 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. Husemann, K., Wolter, M., Büschges, R., Boström, J., Sabel, M., Reifenberger, G. J. Neuropathol. Exp. Neurol. (1999) [Pubmed]
  14. 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. Kumar, R., Smeds, J., Berggren, P., Straume, O., Rozell, B.L., Akslen, L.A., Hemminki, K. Int. J. Cancer (2001) [Pubmed]
  15. Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Franklin, D.S., Godfrey, V.L., O'Brien, D.A., Deng, C., Xiong, Y. Mol. Cell. Biol. (2000) [Pubmed]
  16. Characterization of p18, a component of the lamin B receptor complex and a new integral membrane protein of the avian erythrocyte nuclear envelope. Simos, G., Maison, C., Georgatos, S.D. J. Biol. Chem. (1996) [Pubmed]
  17. Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells. Ariyama, H., Qin, B., Baba, E., Tanaka, R., Mitsugi, K., Harada, M., Nakano, S. J. Cell. Biochem. (2006) [Pubmed]
  18. Identification of lamin B and histones as 1,25-dihydroxyvitamin D3-regulated nuclear phosphoproteins in HL-60 cells. Martell, R.E., Strahler, J.R., Simpson, R.U. J. Biol. Chem. (1992) [Pubmed]
  19. Expression of CDK inhibitor genes in immortalized and carcinoma derived breast cell lines. Zhou, J.N., Linder, S. Anticancer Res. (1996) [Pubmed]
  20. Regulation of the human cyclin-dependent kinase inhibitor p18INK4c by the transcription factors E2F1 and Sp1. Blais, A., Monté, D., Pouliot, F., Labrie, C. J. Biol. Chem. (2002) [Pubmed]
  21. Arsenic trioxide-induced death of neuroblastoma cells involves activation of Bax and does not require p53. Karlsson, J., ØRa, I., Pörn-Ares, I., Påhlman, S. Clin. Cancer Res. (2004) [Pubmed]
  22. Lack of imprinting of three human cyclin-dependent kinase inhibitor genes. Cost, G.J., Thompson, J.S., Reichard, B.A., Lee, J.Y., Feinberg, A.P. Cancer Res. (1997) [Pubmed]
  23. Tumor suppressor INK4: quantitative structure-function analyses of p18INK4C as an inhibitor of cyclin-dependent kinase 4. Li, J., Poi, M.J., Qin, D., Selby, T.L., Byeon, I.J., Tsai, M.D. Biochemistry (2000) [Pubmed]
  24. Analysis of the novel cyclin-dependent kinase 4 and 6 inhibitor gene p18 in lymphoma and leukemia cell lines. Siebert, R., Willers, C.P., Fosså, A., Kloke, O., Nowrousian, M.R., Seeber, S., Opalka, B. Leuk. Res. (1996) [Pubmed]
  25. Identification of novel genes with prognostic value in childhood leukemia using cDNA microarray and quantitative RT-PCR. Hattori, H., Matsuzaki, A., Suminoe, A., Koga, Y., Tashiro, K., Hara, T. Pediatric hematology and oncology. (2006) [Pubmed]
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