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Gene Review

Cdkn2c  -  cyclin-dependent kinase inhibitor 2C (p18,...

Mus musculus

Synonyms: C77269, 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

  • Low p18 expression was frequently observed in different human cancer cell lines and tissues [4].
  • Here we describe the mouse p18 loss-of-function phenotype and a role for p18 in the DNA damage response [4].
  • Inactivation of both p18 alleles caused embryonic lethality, while heterozygous mice showed high susceptibility to spontaneous tumors. p18 was induced and translocated to the nucleus in response to DNA damage [4].
  • T and B lymphocytes develop normally in p18-deficient mice, but both exhibit increased cellularity and a higher proliferative rate upon mitogenic stimulation [2].
  • Chromatin immunoprecipitation studies reveal that menin directly associates with regions of the p27 and p18 promoters and increases methylation of lysine 4 (Lys-4) in histone H3 associated with these promoters [5].

Chemical compound and disease context of Cdkn2c

  • To develop a model of anterior pituitary proliferation to study the pathogenesis of pituitary tumors, we crossed the glycoprotein hormone alpha-subunit (alphaSU)-null mice that develop thyroid-stimulating hormone (TSH) cell hyperplasia with p18-null mice [6].

Biological context of Cdkn2c

  • Additionally, RET2A-dependent p18 repression is required and sufficient to increase cell proliferation [7].
  • Distinctly, there is a remarkable induction of p18INK4c mRNA and protein that was not seen in the closely related nondifferentiating 3T3-C2 cell line, suggesting that p18 induction in 3T3-L1 cells is related to cell differentiation, not cell cycle arrest [8].
  • In the neocortex, p18INK4c was expressed precisely at those developmental stages when neuroblasts switch from a symmetric to an asymmetric pattern of cell division with concomitant increases in their G1 interval [9].
  • The abundance of INK4d mRNA oscillates in a cell-cycle-dependent manner with expression lowest at mid G1 and maximal during S phase [1].
  • Whereas p18INK4c and p19INK4d may regulate pre- and postnatal development, p16INK4a more likely plays a checkpoint function during cell senescence that underscores its selective role as a tumor suppressor [10].

Anatomical context of Cdkn2c


Associations of Cdkn2c with chemical compounds


Other interactions of Cdkn2c


Analytical, diagnostic and therapeutic context of Cdkn2c

  • Reconstituted mice with p18-deficient HSCs under the condition of repetitive proliferative stress (serial transplantation) were followed for >3 years [17].
  • Surprisingly, however, Northern blot analysis yields mRNA for As-p18 not only in the early larval stages, but also the unembryonated egg, third-stage larvae, and ovaries of adult worms, even though the protein is not detectable from any of those sources [15].


  1. Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases. Okuda, T., Hirai, H., Valentine, V.A., Shurtleff, S.A., Kidd, V.J., Lahti, J.M., Sherr, C.J., Downing, J.R. Genomics (1995) [Pubmed]
  2. CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Franklin, D.S., Godfrey, V.L., Lee, H., Kovalev, G.I., Schoonhoven, R., Chen-Kiang, S., Su, L., Xiong, Y. Genes Dev. (1998) [Pubmed]
  3. Silencing of the p18INK4c gene by promoter hypermethylation in Reed-Sternberg cells in Hodgkin lymphomas. Sánchez-Aguilera, A., Delgado, J., Camacho, F.I., Sánchez-Beato, M., Sánchez, L., Montalbán, C., Fresno, M.F., Martín, C., Piris, M.A., García, J.F. Blood (2004) [Pubmed]
  4. The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Park, B.J., Kang, J.W., Lee, S.W., Choi, S.J., Shin, Y.K., Ahn, Y.H., Choi, Y.H., Choi, D., Lee, K.S., Kim, S. Cell (2005) [Pubmed]
  5. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Karnik, S.K., Hughes, C.M., Gu, X., Rozenblatt-Rosen, O., McLean, G.W., Xiong, Y., Meyerson, M., Kim, S.K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation. Lloyd, R.V., Ruebel, K.H., Zhang, S., Jin, L. Am. J. Pathol. (2002) [Pubmed]
  7. Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis. Joshi, P.P., Kulkarni, M.V., Yu, B.K., Smith, K.R., Norton, D.L., Veelen, W., Höppener, J.W., Franklin, D.S. Oncogene (2007) [Pubmed]
  8. Regulation of cyclin-dependent kinase 4 during adipogenesis involves switching of cyclin D subunits and concurrent binding of p18INK4c and p27Kip1. Phelps, D.E., Xiong, Y. Cell Growth Differ. (1998) [Pubmed]
  9. Expression of INK4 inhibitors of cyclin D-dependent kinases during mouse brain development. Zindy, F., Soares, H., Herzog, K.H., Morgan, J., Sherr, C.J., Roussel, M.F. Cell Growth Differ. (1997) [Pubmed]
  10. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Zindy, F., Quelle, D.E., Roussel, M.F., Sherr, C.J. Oncogene (1997) [Pubmed]
  11. p18INK4c and p27KIP1 are required for cell cycle arrest of differentiated myotubes. Myers, T.K., Andreuzza, S.E., Franklin, D.S. Exp. Cell Res. (2004) [Pubmed]
  12. p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver. Luedde, T., Rodriguez, M.E., Tacke, F., Xiong, Y., Brenner, D.A., Trautwein, C. Hepatology (2003) [Pubmed]
  13. Histone deacetylase inhibitors activate INK4d gene through Sp1 site in its promoter. Yokota, T., Matsuzaki, Y., Miyazawa, K., Zindy, F., Roussel, M.F., Sakai, T. Oncogene (2004) [Pubmed]
  14. An intrinsic timer that controls cell-cycle withdrawal in cultured cardiac myocytes. Burton, P.B., Raff, M.C., Kerr, P., Yacoub, M.H., Barton, P.J. Dev. Biol. (1999) [Pubmed]
  15. Secretion of a novel, developmentally regulated fatty acid-binding protein into the perivitelline fluid of the parasitic nematode, Ascaris suum. Mei, B., Kennedy, M.W., Beauchamp, J., Komuniecki, P.R., Komuniecki, R. J. Biol. Chem. (1997) [Pubmed]
  16. Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1. Huang, X., Di Liberto, M., Cunningham, A.F., Kang, L., Cheng, S., Ely, S., Liou, H.C., Maclennan, I.C., Chen-Kiang, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  17. Hematopoietic stem cells are not the direct target of spontaneous leukemic transformation in p18(INK4C)-null reconstituted mice. Yuan, Y., Yu, H., Boyer, M.J., Song, X., Cao, S., Shen, H., Cheng, T. Cancer Res. (2006) [Pubmed]
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