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Gene Review

Cdkn2a  -  cyclin-dependent kinase inhibitor 2A

Rattus norvegicus

Synonyms: Arf, INK4A, MTS1, p16, p16Cdkn2a, ...
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Disease relevance of Cdkn2a


High impact information on Cdkn2a

  • Recent data suggest that many tumors, such as malignant gliomas, have disrupted pRB function, either because of RB-1 gene mutations or as a result of mutations affecting upstream regulators of pRB such as cyclin D1 or p16/INK4a/MTS1 (ref. 1-5) [6].
  • Ectopic expression of p16INK4 blocked entry into S phase of the cell cycle induced by oncogenic Ha-Ras, and this block was relieved by coexpression of a catalytically inactive CDK4 mutant [7].
  • Expression of p16INK4 suppressed cellular transformation of primary rat embryo fibroblasts by oncogenic Ha-Ras and Myc, but not by Ha-Ras and E1a [7].
  • Together, these observations provide direct evidence that p16INK4 can inhibit cell growth [7].
  • Arf mutants lacking conserved amino acid residues 2-14 do not block rRNA synthesis and processing or inhibit cell proliferation [8].

Chemical compound and disease context of Cdkn2a


Biological context of Cdkn2a

  • Comparative genomic in situ hybridization showed that the copy number of rat chromosome RNO5 was not altered in any of the glioma cell lines investigated, indicating that the deletions result from a discrete loss in the region of the p16/Cdkn2a/Ink4a locus [1].
  • We show that DEX induced cell proliferation is paralleled by a decrease in Cdkn2a gene transcripts, suggesting a mechanism for hormone promotion [12].
  • We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors [13].
  • To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging [13].
  • A further goal was to determine whether the aberrant p16 gene methylation seen in human tumors is a conserved event in this animal model [2].

Anatomical context of Cdkn2a


Associations of Cdkn2a with chemical compounds


Regulatory relationships of Cdkn2a

  • These findings suggest that p16INK4 and p21Cip1 function as inhibitors of the proliferation of mesangial cells induced by growth-promoting factors and that deregulated expression of cyclin D1 causes cell cycle disturbances [18].

Other interactions of Cdkn2a


Analytical, diagnostic and therapeutic context of Cdkn2a

  • This discordance could result from the occurrence or selection of p16 dysfunction during cell culture [2].
  • In conclusion, ischemia during transplantation results in telomere shortening and subsequent activation of p21 and p16, whereas senescence-associated beta-galactosidase staining is only present in chronically rejecting kidney grafts [22].
  • Hence, agents that prevented colon cancer decreased the mitotic index and altered the expression of c-myc, p16 and p27 suggesting that modulation in the expression of these genes are potential biomarkers for chemopreventive activity [14].
  • The influx of calcium is likely to play a crucial role in the loss of axonal integrity after rhizotomy, while the alterations in potassium, and perhaps also phosphorus, may contribute to activation of the nonneuronal cells, including the up-regulation of Mts1 expression in astrocytes [23].
  • The p16 methylation status and the presence of p16 protein were analyzed by methylation-specific PCR and immunohistochemistry, respectively [15].


  1. The p16/Cdkn2a/Ink4a gene is frequently deleted in nitrosourea-induced rat glial tumors. Schlegel, J., Piontek, G., Kersting, M., Schuermann, M., Kappler, R., Scherthan, H., Weghorst, C., Buzard, G., Mennel, H. Pathobiology (1999) [Pubmed]
  2. Frequent aberrant methylation of p16INK4a in primary rat lung tumors. Swafford, D.S., Middleton, S.K., Palmisano, W.A., Nikula, K.J., Tesfaigzi, J., Baylin, S.B., Herman, J.G., Belinsky, S.A. Mol. Cell. Biol. (1997) [Pubmed]
  3. Mts1 protein expression in the central nervous system after injury. Kozlova, E.N., Lukanidin, E. Glia (2002) [Pubmed]
  4. Cloning of the 5' upstream region of the rat p16 gene and its role in silencing. Abe, M., Okochi, E., Kuramoto, T., Kaneda, A., Takato, T., Sugimura, T., Ushijima, T. Jpn. J. Cancer Res. (2002) [Pubmed]
  5. Mapping of Ras-related GTP-binding proteins by GTP overlay following two-dimensional gel electrophoresis. Huber, L.A., Ullrich, O., Takai, Y., Lütcke, A., Dupree, P., Olkkonen, V., Virta, H., de Hoop, M.J., Alexandrov, K., Peter, M. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  6. Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector. Parr, M.J., Manome, Y., Tanaka, T., Wen, P., Kufe, D.W., Kaelin, W.G., Fine, H.A. Nat. Med. (1997) [Pubmed]
  7. Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Serrano, M., Gómez-Lahoz, E., DePinho, R.A., Beach, D., Bar-Sagi, D. Science (1995) [Pubmed]
  8. Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing. Sugimoto, M., Kuo, M.L., Roussel, M.F., Sherr, C.J. Mol. Cell (2003) [Pubmed]
  9. Aberrant DNA methylation of E-cadherin and p16 genes in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine. Kato, A., Shimizu, K., Shimoichi, Y., Fujii, H., Honoki, K., Tsujiuchi, T. Mol. Carcinog. (2006) [Pubmed]
  10. Absence of p16, p21 and p53 gene alterations in hepatocellular carcinomas induced by N-nitrosodiethylamine or a choline-deficient L-amino acid-defined diet in rats. Sasaki, Y., Tsujiuchi, T., Murata, N., Kubozoe, T., Tsutsumi, M., Konishi, Y. Cancer Lett. (2000) [Pubmed]
  11. Diminished basal phosphorylation level of phospholamban in the postinfarction remodeled rat ventricle: role of beta-adrenergic pathway, G(i) protein, phosphodiesterase, and phosphatases. Huang, B., Wang, S., Qin, D., Boutjdir, M., El-Sherif, N. Circ. Res. (1999) [Pubmed]
  12. Analysis of mechanisms and frequency of CDKN2A/B gene loss during progression of RAS-transformed rat embryo fibroblast clones. Zhou, J.N., Hashemi, J., Helou, K., Zhang, A., Röhme, D., Zetterberg, A., Levan, G., Linder, S. Somat. Cell Mol. Genet. (1998) [Pubmed]
  13. Ink4a/Arf expression is a biomarker of aging. Krishnamurthy, J., Torrice, C., Ramsey, M.R., Kovalev, G.I., Al-Regaiey, K., Su, L., Sharpless, N.E. J. Clin. Invest. (2004) [Pubmed]
  14. Altered expression of c-myc, p16 and p27 in rat colon tumors and its reversal by short-term treatment with chemopreventive agents. Tao, L., Kramer, P.M., Wang, W., Yang, S., Lubet, R.A., Steele, V.E., Pereira, M.A. Carcinogenesis (2002) [Pubmed]
  15. p16 hypermethylation during gastric carcinogenesis of Wistar rats by N-methyl-N'-nitro-N-nitrosoguanidine. Bai, H., Gu, L., Zhou, J., Deng, D. Mutat. Res. (2003) [Pubmed]
  16. Calcineurin inhibition ameliorates structural, contractile, and electrophysiologic consequences of postinfarction remodeling. Deng, L., Huang, B., Qin, D., Ganguly, K., El-Sherif, N. J. Cardiovasc. Electrophysiol. (2001) [Pubmed]
  17. Phenotypic switching in GH3 rat pituitary tumor cells: linked expression of growth hormone and another hormonally responsive protein. Ivarie, R., Morris, J. DNA (1983) [Pubmed]
  18. Overexpression of cell cycle inhibitors (p16INK4 and p21Cip1) and cyclin D1 using adenovirus vectors regulates proliferation of rat mesangial cells. Terada, Y., Yamada, T., Nakashima, O., Tamamori, M., Ito, H., Sasaki, S., Marumo, F. J. Am. Soc. Nephrol. (1997) [Pubmed]
  19. Assignment of the cyclin-dependent kinase inhibitor genes Cdkn2a and Cdkn2b to rat chromosome bands 5q32-->q34 and 5q31-->q33, respectively by fluorescence in situ hybridization, using small PCR-generated probes. Laes, J.F., Van Vooren, P., Szpirer, J., Szpirer, C. Cytogenet. Cell Genet. (1998) [Pubmed]
  20. Cyclin D1, p16, and retinoblastoma gene regulate mitogenic signaling of endothelin in rat mesangial cells. Terada, Y., Inoshita, S., Nakashima, O., Yamada, T., Tamamori, M., Ito, H., Sasaki, S., Marumo, F. Kidney Int. (1998) [Pubmed]
  21. A possible role for p16INK4 in neuronal cell death after retinal ischemia-reperfusion injury. Kuroiwa, S., Katai, N., Yoshimura, N. Invest. Ophthalmol. Vis. Sci. (1999) [Pubmed]
  22. Telomere shortening and cellular senescence in a model of chronic renal allograft rejection. Joosten, S.A., van Ham, V., Nolan, C.E., Borrias, M.C., Jardine, A.G., Shiels, P.G., van Kooten, C., Paul, L.C. Am. J. Pathol. (2003) [Pubmed]
  23. Effects of dorsal root transection on morphology and chemical composition of degenerating nerve fibers and reactive astrocytes in the dorsal funiculus. Wroblewski, R., Roomans, G.M., Kozlova, E.N. Exp. Neurol. (2000) [Pubmed]
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