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Cell Growth and Development

Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b

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Pages 2915-2925 | Received 26 Jul 1999, Accepted 27 Jan 2000, Published online: 27 Mar 2023

REFERENCES

  • Albright, C. F., Giddings, B. W., Liu, J., Vito, M., and Weinberg, R. A.. 1993. Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase. EMBO J. 12:339–347
  • Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., and Barret, J. C.. 1996. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl. Acad. Sci. USA 93:13742–13747
  • Altschmied, J., and Duschl, J.. 1997. Set of optimized luciferase reporter gene plasmids compatible with widely used CAT vectors. BioTechniques 23:436–438
  • Batova, A., Diccianni, M. B., Yu, J. C., Nobori, T., Link, M. P., Pullen, J., and Yu, A. L.. 1997. Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia. Cancer Res. 57:832–836
  • Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J., and Der, C. J.. 1998. Increasing complexity of Ras signaling. Oncogene 17:1395–1413
  • Chin, L., Pomerantz, J., Polsky, D., Jacobson, M., Cohen, C., Cordon-Cardo, C., Horner, J. W.2nd, and DePinho, R. A.. 1997. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 11:2822–2834
  • Chin, L., Pomerantz, J., and DePinho, R. A.. 1998. The INK4a/ARF tumor suppressor: one gene—two products—two pathways. Trends Biochem. Sci. 23:291–296
  • Cowley, S., Paterson, H., Kemp, P., and Marshall, C. J.. 1994. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841–852
  • D'Adamo, D. R., Novick, S., Kahn, J. M., Leonardi, P., and Pellicer, A.. 1997. rsc: a novel oncogene with structural and functional homology with the gene family of exchange factors for Ral. Oncogene 14:1295–1305
  • Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., Pereira-Smith, O., Peacocke, M., and Campisi, J.. 1995. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. USA 92:9363–9367
  • Downward, J.. 1997. Routine role for Ras. Curr. Biol. 7:R258–R260
  • Erickson, S., Sangfelt, O., Heyman, M., Castro, J., Einhorn, S., and Grandér, D.. 1998. Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence. Oncogene 17:595–602
  • Haber, D. A.. 1997. Splicing into senescence: the curious case of p16 and p19ARF. Cell 91:555–558
  • Hannon, G. J., and Beach, D.. 1994. p15INK4b is a potential effector of TGF-β-induced cell cycle arrest. Nature 371:257–261
  • Hara, K., Yonezawa, K., Sakaue, H., Ando, A., Kotani, K., Kitamura, T., Kitamura, Y., Ueda, H., Stephens, L., Jackson, T. R. et al. 1994. 1-Phosphatidylinositol 3-kinase activity is required for insulin-stimulated glucose transport but not for RAS activation in CHO cells. Proc. Natl. Acad. Sci. USA 91:7415–7419
  • Hartsough, M. T., Frey, R. S., Zipfel, P. A., Buard, A., Cook, S. J., McCormick, F., and Mulder, K. M.. 1996. Altered transforming growth factor β signaling in epithelial cells when Ras activation is blocked. J. Biol. Chem. 271:22368–22375
  • Herman, J. G., Jen, J., Merlo, A., and Baylin, S. B.. 1996. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res. 56:722–727
  • Herman, J. G., Civin, C. I., Issa, J. P., Collector, M. I., Sharkis, S. J., and Baylin, S. B.. 1997. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res. 57:837–841
  • Hitomi, M., and Stacey, D. W.. 1999. Cellular Ras and cyclin D1 are required during different cell cycle periods in cycling NIH 3T3 cells. Mol. Cell. Biol. 19:4623–4632
  • Huschtscha, L. I., and Reddel, R. R.. 1999. p16INK4a and the control of cellular proliferative life span. Carcinogenesis 20:921–926
  • Jeffers, M., and Pellicer, A.. 1994. Identification of multiple promoters within the N-ras proto-oncogene. Biochim. Biophys. Acta 1219:623–635
  • Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V., Stockert, E., Day, R. S.3rd, Johnson, B. E., and Skolnick, M. H.. 1994. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440
  • Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., and Sherr, C. J.. 1997. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91:649–659
  • Katz, M. E., and McCormick, F.. 1997. Signal transduction from multiple Ras effectors. Curr. Opin. Genet. Dev. 7:75–79
  • Kerkhoff, E., and Rapp, U. R.. 1997. Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Mol. Cell. Biol. 17:2576–2586
  • Kerkhoff, E., and Rapp, U. R.. 1998. High-intensity Raf signals convert mitotic cell cycling into cellular growth. Cancer Res. 58:1636–1640
  • Land, J., Parada, L. F., and Weinberg, R. A.. 1983. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304:596–602
  • Li, J. M., Nichols, M. A., Chandrasekharan, S., Xiong, Y., and Wang, X. F.. 1995. Transforming growth factor activates the promoter of cyclin-dependent kinase inhibitor p15INK4B through an Sp1 consensus site. J. Biol. Chem. 270:26750–26753
  • Li, Y., Nichols, M. A., Shay, J. W., and Xiong, Y.. 1994. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 54:6078–6082
  • Lin, A. W., Barradas, M., Stone, J. C., van Aelst, L., Serrano, M., and Lowe, S. W.. 1998. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12:3008–3019
  • Linardopoulos, S., Street, A. J., Quelle, D. E., Parry, D., Peters, G., Sherr, C. J., and Balmain, A.. 1995. Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors. Cancer Res. 55:5168–5172
  • Lloyd, A. C.. 1998. Ras versus cyclin-dependent kinase inhibitors. Curr. Opin. Genet. Dev. 8:43–48
  • Lloyd, A. C., Obermuller, F., Staddon, S., Barth, C. F., McMahon, M., and Land, H.. 1997. Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes Dev. 11:663–677
  • Lois, A. F., Cooper, L. T., Geng, Y., Nobori, T., and Carson, D.. 1995. Expression of the p16 and p15 cyclin-dependent kinase inhibitors in lymphocyte activation and neuronal differentiation. Cancer Res. 55:4010–4013
  • Malumbres, M., and Pellicer, A.. 1998. Ras pathways to cell cycle control and cell transformation. Front. Biosci. 3:887–912
  • Malumbres, M., Pérez de Castro, I., Santos, J., Meléndez, B., Mangues, R., Serrano, M., Pellicer, A., and Fernández-Piqueras, J.. 1997. 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. Oncogene 14:1361–1370
  • Malumbres, M., Mangues, R., Ferrer, N., Lu, S., and Pellicer, A.. 1997. Isolation of high molecular weight DNA for reliable genotyping of transgenic mice. BioTechniques 22:1114–1119
  • Malumbres, M., Pérez de Castro, I., Santos, J., Fernández-Piqueras, J., and Pellicer, A.. 1999. Hypermethylation of the cell cycle inhibitor p15INK4b 3′-untranslated region interferes with its transcriptional regulation in primary lymphomas. Oncogene 18:385–396
  • Matesanz, F., and Pellicer, A.. 1995. In vivo and in vitro analysis of retroviral vectors carrying the N-ras oncogene. Int. J. Oncol. 7:443–451
  • McConnell, B. B., Starborg, M., Brookes, S., and Peters, G.. 1998. Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts. Curr. Biol. 8:351–354
  • Merlo, A., Herman, J. G., Mao, L., Lee, D. J., Gabrielson, E., Burger, P. C., Baylin, S. B., and Sidransky, D.. 1995. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat. Med. 1:686–692
  • Michieli, P., Li, W., Lorenzi, M. V., Miki, T., Zakut, R., Givol, D., and Pierce, J. H.. 1996. Inhibition of oncogene-mediated transformation by ectopic expression p21Waf1 in NIH3T3 cells. Oncogene 12:775–784
  • Missero, C., Di Cunto, F., Kiyokawa, H., Koff, A., and Dotto, G. P.. 1996. The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression. Genes Dev. 10:3065–3075
  • Mulcahy, L. S., Smith, M. R., and Stacey, D. W.. 1985. Requirements for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313:241–243
  • Mulder, K. M., and Morris, S. L.. 1992. Activation of p21ras by transforming growth factor beta in epithelial cells. J. Biol. Chem. 267:5029–5031
  • Olson, M. F., Paterson, H. F., and Marshall, C. J.. 1998. Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature 394:295–299
  • Palmero, I., McConnell, B., Parry, D., Brookes, S., Hara, E., Bates, S., Jat, P., and Peters, G.. 1997. Accumulation of p16INK4a in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status. Oncogene 15:495–503
  • Palmero, I., Pantoja, C., and Serrano, M.. 1998. p19ARF links the tumour suppressor p53 to Ras. Nature 395:125–126
  • Peters, G.. 1994. Stifled by inhibitors. Nature 371:204–205
  • Pollock, P. M., Pearson, J. V., and Hayward, N. K.. 1996. Compilation of somatic mutations of the CDKN2 gene in human cancers: non-random distribution of base substitutions. Genes Chromosomes Cancer 15:77–88
  • Polyak, K., Kato, J. Y., Solomon, M. J., Sherr, C. J., Massague, J., Roberts, J. M., and Koff, A.. 1994. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev. 8:9–22
  • Pumiglia, K. M., and Decker, S. J.. 1997. Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA 94:448–452
  • Quelle, D. E., Zindy, F., Ashmun, R. A., and Sherr, C. J.. 1995. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83:993–1000
  • Quelle, D. E., Ashmun, R. A., Hannon, G. J., Rehberger, P. A., Trono, D., Richter, K. H., Walker, C., Beach, D., Sherr, C. J., and Serrano, M.. 1995. Cloning and characterization of murine p16INK4a and p15INK4b genes. Oncogene 11:635–645
  • Reif, K., Nobles, C. D., Thomas, G., Hall, A., and Cantrell, D. A.. 1996. Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways. Curr. Biol. 6:1445–1455
  • Robertson, K. D., and Jones, P. A.. 1998. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol. Cell. Biol. 18:6457–6473
  • Rodriguez-Viciana, P., Warne, P. H., Khwaja, A., Marte, B. M., Pappin, D., Das, P., Waterfield, M. D., Ridley, A., and Downward, J.. 1997. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89:457–467
  • Ruas, M., and Peters, G.. 1998. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim. Biophys. Acta 1378:F115–F177
  • Ruley, H. E.. 1983. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 304:602–606
  • Sandhu, C., Garbe, J., Bhattacharya, N., Daksis, J., Pan, C. H., Yaswen, P., Koh, J., Slingerland, J. M., and Stampfer, M. R.. 1997. Transforming growth factor β stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells. Mol. Cell. Biol. 17:2458–2467
  • Serrano, M., Hannon, G. J., and Beach, D.. 1993. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707
  • Serrano, M., Gómez-Lahoz, E., DePinho, R. A., Beach, D., and Bar-Sagi, D.. 1995. Inhibition of Ras-induced proliferation and cellular transformation by p16INK4. Science 267:249–252
  • Serrano, M., Lee, H. W., Chin, L., Cordon-Cardo, C., Beach, D., and DePinho, R. A.. 1996. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:27–37
  • Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., and Lowe, S. W.. 1997. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602
  • Sewing, A., Wiseman, B., Lloyd, A. C., and Land, H.. 1997. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol. Cell. Biol. 17:5588–5597
  • Sharpless, N. E., and DePinho, R. A.. 1999. The INK4A/ARF locus and its two gene products. Curr. Opin. Genet. Dev. 9:22–30
  • Sherr, C. J.. 1998. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 12:2984–2991
  • Stone, S., Dayananth, P., Jiang, P., Weaver-Feldhaus, J. M., Tavtigian, S. V., Cannon-Albright, L., and Kamb, A.. 1995. Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. Oncogene 11:987–991
  • Swafford, D. S., Middleton, S. K., Palmisano, W. A., Nikula, K. J., Tesfaigzi, J., Baylin, S. B., Herman, J. G., and Belinsky, S. A.. 1997. Frequent aberrant methylation of p16INK4a in primary rat lung tumors. Mol. Cell. Biol. 17:1366–1374
  • Tan, T.-H., Wallis, J., and Levine, A. J.. 1986. Identification of the p53 protein domain involved in formation of the simian virus 40 large T-antigen–p53 protein complex. J. Virol. 59:574–583
  • Urano, T., Emkey, R., and Feig, L. A.. 1996. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J. 15:810–816
  • Watanabe, H., Pan, Z. Q., Schreiber-Agus, N., DePinho, R. A., Hurwitz, J., and Xiong, Y.. 1998. Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen. Proc. Natl. Acad. Sci. USA 95:1392–1397
  • Weinberg, R. A.. 1997. The cat and mouse games that genes, viruses, and cells play. Cell 88:573–575
  • Westwick, J. K., Cox, A. D., Der, C. J., Cobb, M. H., Hibi, M., Karin, M., and Brenner, D. A.. 1994. Oncogenic Ras activates c-Jun via a separate pathway from the activation of extracellular signal-regulated kinases. Proc. Natl. Acad. Sci. USA 91:6030–6034
  • White, M. A., Nocolette, C., Minden, A., Polverino, A., Van Aelst, L., Karin, M., and Wigler, M. H.. 1995. Multiple Ras functions can contribute to mammalian cell transformation. Cell 80:533–541
  • Wolthuis, R. M., de Ruiter, N. D., Cool, R. H., and Bos, J. L.. 1997. Stimulation of gene induction and cell growth by the Ras effector Rlf. EMBO J. 16:6748–6761
  • Woods, D., Parry, D., Cherwinski, H., Bosch, E., Lees, E., and McMahon, M.. 1997. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol. Cell. Biol. 17:5598–5611
  • Yue, J., Buard, A., and Mulder, K. M.. 1998. Blockade of TGFbeta3 up-regulation of p27Kip1 and p21Cip1 by expression of RasN17 in epithelial cells. Oncogene 17:47–55
  • Zhu, J., Woods, D., McMahon, M., and Bishop, J. M.. 1998. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 12:2997–3007
  • Zhuang, S. M., Schippert, A., Haugen-Strano, A., Wiseman, R. W., and Söderkvist, P.. 1998. Inactivations of p16INK4a-α, p16INK4a-β and p15INK4b genes in 2′,3′-dideoxycytidine- and 1,3-butadiene-induced murine lymphomas. Oncogene 16:803–808
  • Zindy, F., Quelle, D. E., Roussel, M. F., and Sherr, C. J.. 1997. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15:203–211
  • Zindy, F., van Deursen, J., Grosveld, G., Sherr, C. J., and Roussel, M.. 2000. INK4d-deficient mice are fertile despite testicular atrophy. Mol. Cell. Biol. 20:372–378

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