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Gene Review

Cdkn2b  -  cyclin-dependent kinase inhibitor 2B (p15,...

Mus musculus

Synonyms: AV083695, Cyclin-dependent kinase 4 inhibitor B, INK4b, MTS2, p14-INK4b, ...
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Disease relevance of Cdkn2b


High impact information on Cdkn2b

  • We now report on a gene on human chromosome 11, at the junction of the T-cell tumour-associated chromosomal translocation t(11; 14) (p15; q11) and known as the 11p15 gene or Ttg, which is believed to be involved in the pathogenesis of the tumour [6].
  • However, the two anti-DNA antibodies were found to immunoprecipitate viral proteins from retrovirus-infected cells. mAb 512 reacted with gp70, both in cell membrane lysates and in purified form; mAb 319 reacted with gp85, which contains both gp70 and the retroviral protein p15 [7].
  • Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15INK4b messenger RNA in primary cells and are, as a consequence, deficient in immortalization [8].
  • Why downregulation of c-myc expression by TGFbeta is required for rapid activation of p15INK4b has remained unknown [9].
  • While heterologous antisera to purified gp71 and p15 of MuLV reacted to a certain degree with rhabdomyosarcoma virus 114 and rat leukemia virus, natural mouse antibody did not [10].

Chemical compound and disease context of Cdkn2b


Biological context of Cdkn2b


Anatomical context of Cdkn2b


Associations of Cdkn2b with chemical compounds

  • In contrast, homozygous deletions spanning the p16INK4a and p15INK4b loci were observed in only two of 31 1,3-butadiene-induced tumours [1].
  • Like the insulin-activated autophosphorylation of the receptor's beta subunit (on tyrosine), activation of phosphorylation of p15 is specific, with insulin-like growth factors 1 and 2, epidermal growth factor, and platelet-derived growth factor being inactive [17].
  • The temporal kinetic relationship of insulin-activated receptor beta-subunit phosphorylation, followed by the phosphorylation of p15 and then increased hexose uptake rate, is consistent with an intermediary signaling role for pp15 in insulin-stimulated glucose uptake [17].
  • An in-frame stop codon within the new exon, called exon 1beta, leads to translation of a Mr 10,000 protein identical to the NH2 terminus of p15 but contains a novel, basic COOH terminus [18].
  • Similarly, interferon did not affect labeling or chasing of precursor protein carrying the p15 determinants; labeling of p15 itself could not be studied because it does not contain methionine [19].

Physical interactions of Cdkn2b

  • Using a mouse macrophage cell line (Bac1.2F5), we found that most of Cdk4 bound to p15 when cells were in a quiescent state [20].

Regulatory relationships of Cdkn2b

  • Although Cdkn2b (p15(INK4b)) mRNA was expressed in the Myc tumors, many transcripts were aberrant in size and contained only exon 1 [21].
  • Thus, allelic loss and promoter hypermethylation of the p15INK4b gene is particular to radiation-induced lymphoid leukaemias and is independent of p16INK4a and p19ARF gene promoter/exon 1 hypermethylation [22].

Other interactions of Cdkn2b

  • The Ink4b gene (Cdkn2b) encodes p15(Ink4b), a cyclin-dependent kinase inhibitor [23].
  • The activities of these kinases are negatively regulated by a number of proteins, such as p15INK4b, p21WAF1/Cip1, and p27Kip1, that physically associate with cyclins, cyclin-dependent kinases (Cdk), or cyclin-Cdk complexes [24].
  • The significant decrease in p15 expression in tumors provides additional evidence that TGF-beta signaling may be markedly attenuated during colon tumorigenesis [25].
  • On chromosome 4, at least three distinct regions of allelic deletions could be identified: one proximal to 22 cM; the second close to the p16INK4a/p15INK4b locus, which is commonly deleted in various tumors; and the third one in the proximity of Mom1 [26].
  • This was not the case for p15(INK4b) or calretinin (Cdkn2b and Calb2, respectively) [27].

Analytical, diagnostic and therapeutic context of Cdkn2b

  • We studied bone marrow samples of 42 newly diagnosed and untreated patients with acute lymphoblastic leukemia for the incidence of deletions of p16INK4a/p14ARF and p15INK4b using Southern blot analysis and determined the clinical outcome with regard to complete remission (CR) duration, event-free survival, and overall survival [28].
  • Southern blot analysis revealed homozygous deletions of the p16INK4a gene locus in three of the nine lines, along with the genes encoding p15INK4b and p19ARF [29].
  • This protein was shown by immunoprecipitation to have antigenic determinants of MuLV p30, p15, and p10, but not gp70, suggesting that p(75) represents a polyprotein composed of virion core components [30].
  • Expression and analysis of p15 and epitope-tagged p10 in cells by immunohistochemistry showed similar localization of both to the cytoplasm and nucleus in mink epithelial cells and cytoplasmic localization in mouse fibroblasts [18].
  • When analyzed by two-dimensional diagonal gels (nonreducing/reducing), only the I-E bands are revealed by autoradiography, indicating that the putative p15 that associates with I-E may not be accessible to surface labeling [31].


  1. Inactivations of p16INK4a-alpha, p16INK4a-beta and p15INK4b genes in 2',3'-dideoxycytidine- and 1,3-butadiene-induced murine lymphomas. Zhuang, S.M., Schippert, A., Haugen-Strano, A., Wiseman, R.W., Söderkvist, P. Oncogene (1998) [Pubmed]
  2. Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors. Linardopoulos, S., Street, A.J., Quelle, D.E., Parry, D., Peters, G., Sherr, C.J., Balmain, A. Cancer Res. (1995) [Pubmed]
  3. Homozygous codeletion and differential decreased expression of p15INK4b, p16INK4a-alpha and p16INK4a-beta in mouse lung tumor cells. Herzog, C.R., Soloff, E.V., McDoniels, A.L., Tyson, F.L., Malkinson, A.M., Haugen-Strano, A., Wiseman, R.W., Anderson, M.W., You, M. Oncogene (1996) [Pubmed]
  4. Interferon beta increases c-Myc proteolysis in mouse monocyte/macrophage leukemia cells. Hu, X., Bies, J., Wolff, L. Leuk. Res. (2005) [Pubmed]
  5. The Rgr oncogene induces tumorigenesis in transgenic mice. Jiménez, M., Pérez de Castro, I., Benet, M., García, J.F., Inghirami, G., Pellicer, A. Cancer Res. (2004) [Pubmed]
  6. Segmental and developmental regulation of a presumptive T-cell oncogene in the central nervous system. Greenberg, J.M., Boehm, T., Sofroniew, M.V., Keynes, R.J., Barton, S.C., Norris, M.L., Surani, M.A., Spillantini, M.G., Rabbits, T.H. Nature (1990) [Pubmed]
  7. Parallel sets of autoantibodies in MRL-lpr/lpr mice. An anti-DNA, anti-SmRNP, anti-gp70 network. Migliorini, P., Ardman, B., Kaburaki, J., Schwartz, R.S. J. Exp. Med. (1987) [Pubmed]
  8. Repression of p15INK4b expression by Myc through association with Miz-1. Staller, P., Peukert, K., Kiermaier, A., Seoane, J., Lukas, J., Karsunky, H., Möröy, T., Bartek, J., Massagué, J., Hänel, F., Eilers, M. Nat. Cell Biol. (2001) [Pubmed]
  9. TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Seoane, J., Pouponnot, C., Staller, P., Schader, M., Eilers, M., Massagué, J. Nat. Cell Biol. (2001) [Pubmed]
  10. Autogenous immunity to endogenous RNA tumor virus: reactivity of natural immune sera to antigenic determinants of several biologically distinct murine leukemia viruses. Lee, J.C., Ihle, J.N. J. Natl. Cancer Inst. (1975) [Pubmed]
  11. Intracellular transport of the murine leukemia virus during acute infection of NIH 3T3 cells: nuclear import of nucleocapsid protein and integrase. Risco, C., Menéndez-Arias, L., Copeland, T.D., Pinto da Silva, P., Oroszlan, S. J. Cell. Sci. (1995) [Pubmed]
  12. Comparative analysis of Homo sapiens and Mus musculus cyclin-dependent kinase (CDK) inhibitor genes p16 (MTS1) and p15 (MTS2). Jiang, P., Stone, S., Wagner, R., Wang, S., Dayananth, P., Kozak, C.A., Wold, B., Kamb, A. J. Mol. Evol. (1995) [Pubmed]
  13. Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas. Malumbres, M., Pérez de Castro, I., Santos, J., Meléndez, B., Mangues, R., Serrano, M., Pellicer, A., Fernández-Piqueras, J. Oncogene (1997) [Pubmed]
  14. INK4d-deficient mice are fertile despite testicular atrophy. Zindy, F., van Deursen, J., Grosveld, G., Sherr, C.J., Roussel, M.F. Mol. Cell. Biol. (2000) [Pubmed]
  15. 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]
  16. Hypermethylation of the cell cycle inhibitor p15INK4b 3'-untranslated region interferes with its transcriptional regulation in primary lymphomas. Malumbres, M., Pérez de Castro, I., Santos, J., Fernández Piqueras, J., Pellicer, A. Oncogene (1999) [Pubmed]
  17. Insulin-activated tyrosine phosphorylation of a 15-kilodalton protein in intact 3T3-L1 adipocytes. Bernier, M., Laird, D.M., Lane, M.D. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  18. Cloning and characterization of p10, an alternatively spliced form of p15 cyclin-dependent kinase inhibitor. Tsubari, M., Tiihonen, E., Laiho, M. Cancer Res. (1997) [Pubmed]
  19. Synthesis and cleavage processing of oncornavirus proteins during interferon inhibition of virus particle release. Shapiro, S.Z., Strand, M., Billiau, A. Infect. Immun. (1977) [Pubmed]
  20. Cdk4 activation is dependent on the subunit rearrangement in the complexes. Takahashi, H., Menjo, M., Kaneko, Y., Ikeda, K., Matsushime, H., Nakanishi, M. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  21. Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15(INK4b) normally associated with differentiation. Schmidt, M., Koller, R., Haviernik, P., Bies, J., Maciag, K., Wolff, L. Oncogene (2001) [Pubmed]
  22. Allelic loss and promoter hypermethylation of the p15INK4b gene features in mouse radiation-induced lymphoid - but not myeloid - leukaemias. Cleary, H.J., Boulton, E., Plumb, M. Leukemia (1999) [Pubmed]
  23. Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15(Ink4b)-deficient mice. Wolff, L., Garin, M.T., Koller, R., Bies, J., Liao, W., Malumbres, M., Tessarollo, L., Powell, D., Perella, C. Oncogene (2003) [Pubmed]
  24. TGF-beta 1 induces the cyclin-dependent kinase inhibitor p27Kip1 mRNA and protein in murine B cells. Kamesaki, H., Nishizawa, K., Michaud, G.Y., Cossman, J., Kiyono, T. J. Immunol. (1998) [Pubmed]
  25. Aberrant transforming growth factor-beta signaling in azoxymethane-induced mouse colon tumors. Guda, K., Giardina, C., Nambiar, P., Cui, H., Rosenberg, D.W. Mol. Carcinog. (2001) [Pubmed]
  26. Elevated frequency of loss of heterozygosity in mammary tumors arising in mouse mammary tumor virus/neu transgenic mice. Cool, M., Jolicoeur, P. Cancer Res. (1999) [Pubmed]
  27. Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. Niculescu, M.D., Craciunescu, C.N., Zeisel, S.H. FASEB J. (2006) [Pubmed]
  28. The prognostic significance of p16INK4a/p14ARF and p15INK4b deletions in adult acute lymphoblastic leukemia. Faderl, S., Kantarjian, H.M., Manshouri, T., Chan, C.Y., Pierce, S., Hays, K.J., Cortes, J., Thomas, D., Estrov, Z., Albitar, M. Clin. Cancer Res. (1999) [Pubmed]
  29. Inhibition of T-cell acute lymphoblastic leukemia proliferation in vivo by re-expression of the p16INK4a tumor suppressor gene. Schoppmeyer, K., Norris, P.S., Haas, M. Neoplasia (1999) [Pubmed]
  30. A core polyprotein of murine leukemia virus on the surface of mouse leukemia cells. Tung, J.S., Yoshiki, T., Fleissner, E. Cell (1976) [Pubmed]
  31. Molecular associations of class II MHC antigens in mitogen-stimulated B cells. Wolfert, R.L., Goodman, M.G., Weigle, W.O. J. Immunol. (1985) [Pubmed]
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