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Cdkn2a  -  cyclin-dependent kinase inhibitor 2A

Mus musculus

Synonyms: ARF-INK4a, Arf, CDK4I, Cyclin-dependent kinase 4 inhibitor A, Cyclin-dependent kinase inhibitor 2A, isoform 3, ...
 
 
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Disease relevance of Cdkn2a

  • Mutations of genes involved in human melanoma have been recapitulated with some unexpected results, particularly with respect to the role of the two transcripts (Ink4a and Arf) encoded by the Cdkn2a locus [1].
  • Secondly, genetic resistance to lung tumor formation appears to segregate with one particular haplotype, which also is deleted preferentially in lung adenocarcinomas of Cdkn2a heterozygous mice [2].
  • Loss of p16INK4a results in increased glucocorticoid receptor activity during fibrosarcoma development [3].
  • Because Tp53 mutations are a common feature of the multistep pre-B cell transformation process mediated by Abelson murine leukemia virus (Ab-MLV), we examined the possibility that proteins encoded by the Ink4a/Arf locus also play a role in Abelson virus transformation [4].
  • Importantly, exogenous p16(INK4a) introduced by cotransfection is sufficient to reduce GR activity in FS cells, without affecting GR activity in p16-positive aggressive fibromatosis cells [3].
  • Taken together, results from this novel UV-inducible melanoma model suggest that NER loss, in conjunction with Ink4a-Arf inactivation, can drive melanoma photocarcinogenesis possibly through signature Kras mutagenesis [5].
  • Ink4a/Arf-deficient relapses resembled p53-deficient relapses in that both displayed morphologic and molecular hallmarks of an epithelial-to-mesenchymal transition (EMT) [6].
 

Psychiatry related information on Cdkn2a

  • Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2a gene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn strain [7].
 

High impact information on Cdkn2a

  • We conclude that inactivation or depletion of the Wip1 phosphatase with resultant p38 MAPK activation suppresses tumor appearance by modulating the Cdkn2a tumor-suppressor locus [8].
  • In addition, the tumor-suppressor pathway Cdkn2a/Rb1 has also been implicated as a barrier to immortalization [9].
  • A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy [10].
  • Insertional mutagenesis by the latent retrovirus was synergistic with loss of Cdkn2a expression, as indicated by a marked acceleration in the development of both myeloid and lymphoid tumors [11].
  • Using this system, we show that growth arrest by the cell cycle inhibitor p16 is reversible and dependent on its continuous expression [12].
 

Chemical compound and disease context of Cdkn2a

 

Biological context of Cdkn2a

  • We show posterior transformations of the axial skeleton and premature senescence of mouse embryonic fibroblasts associated with derepression of Hox cluster genes and Cdkn2a genes, respectively [17].
  • Differences in mammary tumor occurrence among genotypes for Prkdc and Cdkn2a in N2 mice were not statistically significant [18].
  • The Cdkn2a (p16(INK4a)) gene was generally not expressed in either tumor type, an observation explained by methylation or deletion in the promoter region [19].
  • The Cdkn2a locus on chromosome 4 was inactivated by hypermethylation in 55% of all tumors [20].
  • Analysis of exons 1 and 2 of the Cdkn2a gene by single-strand conformation polymorphism and sequence analyses revealed mutations in exon 2 in 7% of the tumors examined [21].
 

Anatomical context of Cdkn2a

  • Compared with wild-type MEFs, p16Ink4a-null MEFs exhibited an increased rate of immortalization, although this rate was less than that observed previously for cells null for Ink4a/Arf, p19Arf or p53 (refs 4, 5) [22].
  • We also detected no intragenic mutations of either gene in 44 tumors that displayed loss of heterozygosity at the p16INK4a locus or in any of the cell lines [23].
  • We examined 99 lung adenocarcinomas of C3H/HeJ x A/J F1(C3AF1) and A/J x C3H/HeJ F1(AC3F1) mouse hybrids and 18 (13 metastatic, 5 nonmetastatic) tumorigenic mouse lung epithelial cell lines for p15INK4b and p16INK4a gene inactivation [23].
  • Following pristane treatment, BALB/c p16 mRNA levels in B cells were lower than that in DBA/2 or C.D2-Pctr1, a resistant BALB/c congenic strain that harbors DBA/2 chromatin surrounding the p16 locus [24].
  • Loss of p19ARF enhances the defects of Mdm2 overexpression in the mammary gland [25].
 

Associations of Cdkn2a 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 [13].
  • Finally, treatment of mice bearing genetically defined tumors with nontoxic doses of 5-aza-dC results in therapeutical responses only on tumors lacking p53, but not on tumors lacking p19ARF [26].
  • In fact, L-778,123 is more effective in inhibiting primary lung progression in mice with a p53 mutation and/or an Ink4a/Arf deletion than in wild-type animals [27].
  • Unlike preB cells from wild-type mice, those from mice lacking Arf alone could be propagated indefinitely when placed onto stromal feeder layers engineered to produce IL-7 [28].
  • We used p19ARF knockout mouse embryo fibroblasts to show that DNA damage and microtubule disruption require p19ARF to induce p53 responses, whereas ribonucleotide depletion and inhibition of RNA synthesis by low doses of actinomycin D do not [29].
 

Physical interactions of Cdkn2a

  • Thus, distinct E2F complexes directly contribute to the normal repression and oncogenic activation of Arf [30].
  • These observations show that specificity exists between Cdk4/6-cyclin D complexes and their ability to be targeted by p16 [31].
  • Moreover, three AP1-like binding sites were identified in the p16 promoter through which JunB directly activates p16 transcription [32].
  • These data argue that p27 can also cooperatively interact with p16 to inhibit DNA synthesis in hepatocytes [33].
  • BACKGROUND: Arf GAPs are multidomain proteins that function in membrane traffic by inactivating the GTP binding protein Arf1 [34].
 

Regulatory relationships of Cdkn2a

  • Consistent with this notion, Arf mutation suppresses the activation of p53 and p21(Cip1) in E2f3-deficient MEFs [30].
  • Here, we show that E2F directly participates in the transcriptional control of Arf in both normal and transformed cells [30].
  • Thus, these cyclin dependent kinase inhibitor genes may play a significant role in chemically induced mouse lymphomas and support the contention of tumour suppressor activity for the p19ARF protein encoded by the p16INK4a-beta gene [13].
  • The alternative reading frame product (p19ARF) of the mouse INK4a/ARF locus is induced by oncoproteins such as Myc and E1A as part of a checkpoint response that limits cell cycle progression in response to hyperproliferative signals [35].
  • The Polycomb group (PcG) gene Bmi1 promotes cell proliferation and stem cell self-renewal by repressing the Ink4a/Arf locus [36].
 

Other interactions of Cdkn2a

  • E2f3 loss is sufficient to derepress Arf, triggering activation of p53 and expression of p21(Cip1) [30].
  • Specifically, we observe recruitment of the endogenous activating E2Fs, E2F1, and E2F3a, to the Arf promoter [30].
  • Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics [30].
  • Most importantly, however, overexpression of the cyclin D-dependent kinase inhibitor p16INK4 protects neurons from apoptotic cell death, demonstrating that activation of endogenous cyclin D1-dependent kinases is essential during neuronal apoptosis [37].
  • Prior expression of cyclin E allows S-phase entry and long-term proliferation in the presence of p16 [38].
 

Analytical, diagnostic and therapeutic context of Cdkn2a

  • Treatment with ATB resulted in an approximately 40% decrease in tumor multiplicity and a 70% decrease in tumor load in both wild-type mice and in mice with a loss of the Ink4a/Arf tumor suppressor genes [39].
  • Western blot analysis indicated a constant expression of p27 protein but slightly decreased levels of p16 in these transformed clones [40].
  • Then, we investigated the status of the mouse homolog of p16/CDKN2 gene (mouse p16) on chromosome 4 by the comparative multiplex PCR method, and detected the homozygous deletion in two liver epithelial cell lines [41].
  • The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs [42].
  • However, the efficacy of budesonide against lung tumor progression decreased from 94 to 77% (P = 0.07) in mice with alterations in both p53 and Ink4A/Arf in a 40-week chemoprevention assay [43].

References

  1. Pathways to melanoma development: lessons from the mouse. Walker, G.J., Hayward, N.K. J. Invest. Dermatol. (2002) [Pubmed]
  2. Cdkn2a encodes functional variation of p16INK4a but not p19ARF, which confers selection in mouse lung tumorigenesis. Herzog, C.R., Noh, S., Lantry, L.E., Guan, K.L., You, M. Mol. Carcinog. (1999) [Pubmed]
  3. Loss of p16INK4a results in increased glucocorticoid receptor activity during fibrosarcoma development. Roca, R., Kypta, R.M., Vivanco, M.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. p19(Arf) induces p53-dependent apoptosis during abelson virus-mediated pre-B cell transformation. Radfar, A., Unnikrishnan, I., Lee, H.W., DePinho, R.A., Rosenberg, N. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  5. Loss of xeroderma pigmentosum C (Xpc) enhances melanoma photocarcinogenesis in Ink4a-Arf-deficient mice. Yang, G., Curley, D., Bosenberg, M.W., Tsao, H. Cancer Res. (2007) [Pubmed]
  6. Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16 Ink4a loss. Debies, M.T., Gestl, S.A., Mathers, J.L., Mikse, O.R., Leonard, T.L., Moody, S.E., Chodosh, L.A., Cardiff, R.D., Gunther, E.J. J. Clin. Invest. (2008) [Pubmed]
  7. Efficiency alleles of the Pctr1 modifier locus for plasmacytoma susceptibility. Zhang, S.L., DuBois, W., Ramsay, E.S., Bliskovski, V., Morse, H.C., Taddesse-Heath, L., Vass, W.C., DePinho, R.A., Mock, B.A. Mol. Cell. Biol. (2001) [Pubmed]
  8. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Bulavin, D.V., Phillips, C., Nannenga, B., Timofeev, O., Donehower, L.A., Anderson, C.W., Appella, E., Fornace, A.J. Nat. Genet. (2004) [Pubmed]
  9. A role for the Rb family of proteins in controlling telomere length. García-Cao, M., Gonzalo, S., Dean, D., Blasco, M.A. Nat. Genet. (2002) [Pubmed]
  10. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Schmitt, C.A., Fridman, J.S., Yang, M., Lee, S., Baranov, E., Hoffman, R.M., Lowe, S.W. Cell (2002) [Pubmed]
  11. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Lund, A.H., Turner, G., Trubetskoy, A., Verhoeven, E., Wientjens, E., Hulsman, D., Russell, R., DePinho, R.A., Lenz, J., van Lohuizen, M. Nat. Genet. (2002) [Pubmed]
  12. Tetracycline-regulatable factors with distinct dimerization domains allow reversible growth inhibition by p16. Rossi, F.M., Guicherit, O.M., Spicher, A., Kringstein, A.M., Fatyol, K., Blakely, B.T., Blau, H.M. Nat. Genet. (1998) [Pubmed]
  13. 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]
  14. p27 deficiency desensitizes Rb-/- cells to signals that trigger apoptosis during pituitary tumor development. Carneiro, C., Jiao, M.S., Hu, M., Shaffer, D., Park, M., Pandolfi, P.P., Cordon-Cardo, C., Koff, A. Oncogene (2003) [Pubmed]
  15. Combination of gemcitabine and Ad5/3-Delta24, a tropism modified conditionally replicating adenovirus, for the treatment of ovarian cancer. Raki, M., Kanerva, A., Ristimaki, A., Desmond, R.A., Chen, D.T., Ranki, T., Sarkioja, M., Kangasniemi, L., Hemminki, A. Gene Ther. (2005) [Pubmed]
  16. Melanocyte development and malignant melanoma. Goding, C.R. Forum (Genoa, Italy) (2000) [Pubmed]
  17. Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes. Isono, K., Fujimura, Y., Shinga, J., Yamaki, M., O-Wang, J., Takihara, Y., Murahashi, Y., Takada, Y., Mizutani-Koseki, Y., Koseki, H. Mol. Cell. Biol. (2005) [Pubmed]
  18. BALB/c alleles for Prkdc and Cdkn2a interact to modify tumor susceptibility in Trp53+/- mice. Blackburn, A.C., Brown, J.S., Naber, S.P., Otis, C.N., Wood, J.T., Jerry, D.J. Cancer Res. (2003) [Pubmed]
  19. 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]
  20. Pattern of secondary genomic changes in pancreatic tumors of Tgf alpha/Trp53+/- transgenic mice. Schreiner, B., Baur, D.M., Fingerle, A.A., Zechner, U., Greten, F.R., Adler, G., Sipos, B., Klöppel, G., Hameister, H., Schmid, R.M. Genes Chromosomes Cancer (2003) [Pubmed]
  21. Role of tumor suppressor genes in transplacental lung carcinogenesis. Rollins, L.A., Leone-Kabler, S., O'Sullivan, M.G., Miller, M.S. Mol. Carcinog. (1998) [Pubmed]
  22. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Sharpless, N.E., Bardeesy, N., Lee, K.H., Carrasco, D., Castrillon, D.H., Aguirre, A.J., Wu, E.A., Horner, J.W., DePinho, R.A. Nature (2001) [Pubmed]
  23. 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]
  24. p16 INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB. Zhang, S., Qian, X., Redman, C., Bliskovski, V., Ramsay, E.S., Lowy, D.R., Mock, B.A. Oncogene (2003) [Pubmed]
  25. Loss of p19ARF enhances the defects of Mdm2 overexpression in the mammary gland. Foster, C.J., Lozano, G. Oncogene (2002) [Pubmed]
  26. The absence of p53 is critical for the induction of apoptosis by 5-aza-2'-deoxycytidine. Nieto, M., Samper, E., Fraga, M.F., González de Buitrago, G., Esteller, M., Serrano, M. Oncogene (2004) [Pubmed]
  27. Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. Zhang, Z., Wang, Y., Lantry, L.E., Kastens, E., Liu, G., Hamilton, A.D., Sebti, S.M., Lubet, R.A., You, M. Oncogene (2003) [Pubmed]
  28. Differential effects of p19(Arf) and p16(Ink4a) loss on senescence of murine bone marrow-derived preB cells and macrophages. Randle, D.H., Zindy, F., Sherr, C.J., Roussel, M.F. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  29. Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. Khan, S.H., Moritsugu, J., Wahl, G.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  30. Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Aslanian, A., Iaquinta, P.J., Verona, R., Lees, J.A. Genes Dev. (2004) [Pubmed]
  31. Cdk6-cyclin D3 activity in murine ES cells is resistant to inhibition by p16(INK4a). Faast, R., White, J., Cartwright, P., Crocker, L., Sarcevic, B., Dalton, S. Oncogene (2004) [Pubmed]
  32. JunB suppresses cell proliferation by transcriptional activation of p16(INK4a) expression. Passegué, E., Wagner, E.F. EMBO J. (2000) [Pubmed]
  33. Hepatitis B virus X protein increases expression of p21(Cip-1/WAF1/MDA6) and p27(Kip-1) in primary mouse hepatocytes, leading to reduced cell cycle progression. Qiao, L., Leach, K., McKinstry, R., Gilfor, D., Yacoub, A., Park, J.S., Grant, S., Hylemon, P.B., Fisher, P.B., Dent, P. Hepatology (2001) [Pubmed]
  34. A BAR domain in the N terminus of the Arf GAP ASAP1 affects membrane structure and trafficking of epidermal growth factor receptor. Nie, Z., Hirsch, D.S., Luo, R., Jian, X., Stauffer, S., Cremesti, A., Andrade, J., Lebowitz, J., Marino, M., Ahvazi, B., Hinshaw, J.E., Randazzo, P.A. Curr. Biol. (2006) [Pubmed]
  35. Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function. Kamijo, T., van de Kamp, E., Chong, M.J., Zindy, F., Diehl, J.A., Sherr, C.J., McKinnon, P.J. Cancer Res. (1999) [Pubmed]
  36. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Bruggeman, S.W., Valk-Lingbeek, M.E., van der Stoop, P.P., Jacobs, J.J., Kieboom, K., Tanger, E., Hulsman, D., Leung, C., Arsenijevic, Y., Marino, S., van Lohuizen, M. Genes Dev. (2005) [Pubmed]
  37. Cyclin D1 is an essential mediator of apoptotic neuronal cell death. Kranenburg, O., van der Eb, A.J., Zantema, A. EMBO J. (1996) [Pubmed]
  38. Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. Alevizopoulos, K., Vlach, J., Hennecke, S., Amati, B. EMBO J. (1997) [Pubmed]
  39. Cancer chemopreventive activity of a mixture of Chinese herbs (antitumor B) in mouse lung tumor models. Zhang, Z., Wang, Y., Yao, R., Li, J., Yan, Y., La Regina, M., Lemon, W.L., Grubbs, C.J., Lubet, R.A., You, M. Oncogene (2004) [Pubmed]
  40. Overexpression of p21 protein in radiation-transformed mouse 10T(1/2) cell clones. Krolewski, B., Little, J.B. Mol. Carcinog. (2000) [Pubmed]
  41. Homozygous deletion of mouse homolog of p16/CDKN2 gene on chromosome 4 in mouse liver epithelial cells in culture. Miyasaka, K., Kawauchi, S. Biol. Pharm. Bull. (1996) [Pubmed]
  42. 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]
  43. Mice with alterations in both p53 and Ink4a/Arf display a striking increase in lung tumor multiplicity and progression: differential chemopreventive effect of budesonide in wild-type and mutant A/J mice. Wang, Y., Zhang, Z., Kastens, E., Lubet, R.A., You, M. Cancer Res. (2003) [Pubmed]
 
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