Role of the RB Tumor Suppressor in Cancer

  • Lili Yamasaki
Part of the Cancer Treatment and Research book series (CTAR, volume 115)


Apart from their coordinated inactivation by DNA tumor viral oncoproteins, the pRB and p53 tumor suppressor pathways were not known to be connected ten years ago. Within the last decade, our appreciation of how these pathways ate interconnected has grown substantially. The checks and balances that exist between pRB and p53 involve the regulation of the G1/S transition and its checkpoints, and much of this is under the control of the E2F transcription factor family. Following DNA damage, the p53-dependent induction of p21CIP1 regulates cyclin E/Cdk2 and cyclin A/Cdk2 complexes both of which phosphorylate pRB, leading to E2F-mediated activation. Similarly, E2Fl-dependent induction of p19ARF antagonizes the ability of mdm2 to degrade p53, leading to p53 stabilization and potentially p53-mediated apoptosis or cell cycle arrest. From the existing mouse models discussed above, we also know that proliferation, cell death and differentiation of distinct tissues are also intimately linked through entrance and exit from the cell cycle, and thus through pRB and p53 pathways. Virtually all human tumors deregulate either the pRB or p53 pathway, and often times both pathways simultaneously, which is critical for crippling cellular defense against neoplasia. The next decade of cancer research will likely see these two tumor suppressor pathways only merge even more.


Retinoblastoma Protein Retinoblastoma Gene Tumor Suppressor Pathway Retinoblastoma Tumor Suppressor INK4 Family 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams, M. R., Sears, R., Nuckols, F., Leone, G., and Nevins, J. R. 2000. Complex transcriptional regulatory mechanisms control expression of E2F3 locus. Mol Cell Biol 20:, 3633–9.CrossRefPubMedGoogle Scholar
  2. Ashizawa, S., Nishizawa, H., Yamada, M., Higashi, H., Kondo, T., Ozawa, H., Kakita, A., and Hatakeyama, M. Biol Chem 2001] Apr. 6. Collective inhibition of pRB family proteins by phosphorylation in cells with p16INK4a loss or cyclin E overexpression. J Biol Chem 276:, 11362–70.Google Scholar
  3. Bates, S., Phillips, A. C., Clark, P. A., Stott, F., Peters, G., Ludwig, R. L., and Vousden, K. H. 1998. p14ARF links the tumour suppressors RB and p53. Nature 395:, 124–5.PubMedGoogle Scholar
  4. Bignon, Y. J., Chen, Y., Chang, C. Y., Riley, D. J., Windle, J. J., Mellon, P. L., and Lee, W. H. 1993. Expression of a retinoblastoma transgene results in dwarf mice. Genes Dev 7:, 1654–62.PubMedGoogle Scholar
  5. Bookstein, R., Rio, P., Madreperla, S. A., Hong, F., Allred, C., Grizzle, W. E., and Lee, W. H. 1990. Promoter deletion and loss of retinoblastoma gene expression in human prostate carcinoma. Proc Natl Acad Sci U S A 87:, 7762–6.PubMedGoogle Scholar
  6. Bookstein, R., Shew, J. Y., Chen, P. L., Scully, P., and Lee, W. H. 1990. Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 247:, 712–5.PubMedGoogle Scholar
  7. Bortner, O. M., and Rosenberg, M. P. 1997. Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 17:, 453–9.PubMedGoogle Scholar
  8. Brehm, A., Miska, E. A., McCance, D. J., Reid, J. L., Bannister, A, J., and Kouzarides, T. 1998. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391:, 597–601.PubMedGoogle Scholar
  9. Brown, V. D., and Gallie, B. L. 2002. The B-Domain Lysine Patch of pRB Is Required for Binding to Large T Antigen and Release of E2F by Phosphorylation. Mol. Cell. Biol. 22:, 1390–401.PubMedGoogle Scholar
  10. Brugarolas, J., Bronson, R. T., and Jacks, T. 1998. p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells. J Cell Biol 141:, 503–14.CrossRefPubMedGoogle Scholar
  11. Brugarolas, J., Chandrasekaran, C., Gordon, J. I., Beach, D., Jacks, T., and Hannon, G. J. 1995. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377:, 552–7.CrossRefPubMedGoogle Scholar
  12. Buchkovich, K., Duffy, L. A., and Harlow, E. 1989. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 58:, 1097–105.CrossRefPubMedGoogle Scholar
  13. Carrano, A. C., Eytan, E., Hershko, A., and Pagano, M. 1999. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1:, 193–9.CrossRefPubMedGoogle Scholar
  14. Chan, H. M., Krstic-Demonacos, M., Smith, L., Demonacos, C., and La Thangue, N. B. 2001. Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Cell Biol 3:, 667–74.CrossRefPubMedGoogle Scholar
  15. Chen, P. L., Riley, D. J., Chen, Y., and Lee, W. H. 1996. Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs. Genes Dev 10:, 2794–804.PubMedGoogle Scholar
  16. Chen, P. L., Riley, D. J., Chen-Kiang, S., and Lee, W. H. 1996. Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6. Proc Natl Acad Sci U S A 93:, 465–9.PubMedGoogle Scholar
  17. Chen, P. L., Scully, P., Shew, J. Y., Wang, J. Y., and Lee, W. H. 1989. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell 58:, 1193–8.CrossRefPubMedGoogle Scholar
  18. Cheng, M., Olivier, P., Diehl, J. A., Fero, M., Roussel, M. F., Roberts, J. M., and Sherr, C. J. 1999. The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine flbroblasts. Embo J 18:, 1571–83.CrossRefPubMedGoogle Scholar
  19. Chilosi, M., Doglioni, C., Yan, Z., Lestani, M., Menestrina, F., Sorio, C., Benedetti, A., Vinante, F., Pizzolo, G., and Inghirami, G. 1998. Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia. Am J Pathol 152:, 209–17.PubMedGoogle Scholar
  20. Clarke, A. R., Maandag, E. R., van Roon, M., van der Lugt, N. M., van der Valk, M., Hooper, M. L., Berns, A., and te Riele, H. 1992. Requirement for a functional Rb-1 gene in murine development. Nature 359:, 328–30.CrossRefPubMedGoogle Scholar
  21. Claudio, P. P., Howard, C. M., Pacilio, C., Cinti, C., Romano, G., Minimo, C., Maraldi, N. M., Minna, J. D., Gelbert, L., Leoncini, L., Tosi, G. M., Hicheli, P., Caputi, M., Giordano, G. G., and Giordano, A. 2000. Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. Cancer Res 60:, 372–82.PubMedGoogle Scholar
  22. Cloud, J. E., Rogers, C., Reza, T. L., Ziebold, U., Stone, J. R., Picard, M. H., Caron, A. M., Bronson, R. T., and Lees, J. A. 2002. Mutant Mouse Models Reveal the Relative Roles of E2F1 and E2F3 In Vivo. Mol Cell Biol 22:, 2663–2672.CrossRefPubMedGoogle Scholar
  23. Cobrinik, D., Lee, M. H., Hannon, G., Mulligan, G., Bronson, R. T., Dyson, N., Harlow, E., Beach, D., Weinberg, R. A., and Jacks, T. 1996. Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev 10:, 1633–44.PubMedGoogle Scholar
  24. Corcoran, M. M., Mould, S. J., Orchard, J. A., Ibbotson, R. E., Chapman, R. M., Boright, A. P., Platt, C., Tsui, L. C., Scherer, S. W., and Oscier, D, G. 1999. Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations. Oncogene 18:, 6271–7.CrossRefPubMedGoogle Scholar
  25. Cotran R.S., Kumar, V., and Robbins, S. L. (1994). Pathologic Basis of Disease, 5th. Edition, F. J. Schoen, ed. (Philadelphia: W. B. Saunders Company).Google Scholar
  26. Dannenberg, J. H., van Rossum, A., Schuijff, L., and te Riele, H. 2000. Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev 14:, 3051–64.CrossRefPubMedGoogle Scholar
  27. DeCaprio, J. A., Ludlow, J. W., Figge, J., Shew, J. Y., Huang, C. M., Lee, W. H., Marsilio, E., Paucha, E., and Livingston, D. M. 1988. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54:, 275–83.Google Scholar
  28. DeCaprio, J. A., Ludlow, J. W., Lynch, D., Furukawa, Y., Griffin, J., Piwnica-Worms, H., Huang, C. M., and Livingston, D.M. 1989. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell 58:, 1085–95.Google Scholar
  29. DeGregori, J., Leone, G., Miron, A., Jakoi, L., and Nevins, J. R. 1997. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci U S A 94:, 7245–50.Google Scholar
  30. Deng, C., Zhang, P., Harper, J. W., Elledge, S. J., and Leder, P. 1995. Mice lacking p21CIP1/WAFl undergo normal development, but are defective in G1 checkpoint control. Cell 82:, 675–84.CrossRefPubMedGoogle Scholar
  31. Dick, F. A., Sailhamer, E., and Dyson, N. J. 2000. Mutagenesis of the pRB pocket reveals that cell cycle arrest functions are separable from binding to viral oncoproteins. Mol Cell Biol 20:, 3715–27.CrossRefPubMedGoogle Scholar
  32. Dowdy, S. F., Hinds, P. W., Louie, K., Reed, S. I., Arnold, A., and Weinberg, R. A. 1993. Physical interaction of the retinoblastoma protein with human D cyclins. Cell 73:, 499–511.CrossRefPubMedGoogle Scholar
  33. Dryja, T. P., Rapaport, J. M., Joyce, J. M., and Petersen, R, A, 1986. Molecular detection of deletions involving band q14 of chromosome 13 in retinoblastomas. Proc Natl Acad Sci U S A 83:, 7391–4.PubMedGoogle Scholar
  34. Dryja, T. P., Rapaport, J. M., Weichselbaum, R., and Bruns, G. A. 1984. Chromosome 13 restriction fragment length polymorphisms. Hum Genet 65:, 320–4.CrossRefPubMedGoogle Scholar
  35. Dunaief, J. L., Strober, B. E., Guha, S., Khavari, P. A., Alin, K., Luban, J., Begemann, M., Crabtree, G. R., and Goff, S. P. 1994. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79:, 119–30.CrossRefPubMedGoogle Scholar
  36. Dunn, J. M., Phillips, R. A., Becker, A. J., and Gallie, B. L. 1988. Identification of germline and somatic mutations affecting the retinoblastoma gene. Science 241:, 1797–800.PubMedGoogle Scholar
  37. Durfee, T., Becherer, K., Chen, P. L., Yen, S. H., Yang, Y., Kilburn, A. E., Lee, W. H., and Elledge, S. J. 1993. The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes Dev 7:, 555–69.PubMedGoogle Scholar
  38. Dynlacht, B. D., Flores, O., Lees, J. A., and Harlow, E. 1994. Differential regulation of E2F transactivation by cyclin/cdk2 complexes. Genes Dev 8:, 1772–86.PubMedGoogle Scholar
  39. Dyson, N. 1998. The regulation of E2F by pRB-family proteins. Genes Dev 12:, 2245–62.PubMedGoogle Scholar
  40. Dyson, N., Howley, P. M., Munger, K., and Harlow, E. 1989. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:, 934–7.PubMedGoogle Scholar
  41. el-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B,, Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., and Vogelstein, B. 1993. WAF1, a potential mediator of p53 tumor suppression. Cell 75:, 817–25.CrossRefPubMedGoogle Scholar
  42. Ewen, M. E., Sluss, H. K., Sherr, C. J., Matsushime, H., Kato, J., and Livingston, D. M. 1993. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell 73:, 487–97.CrossRefPubMedGoogle Scholar
  43. Ewen, M. E., Xing, Y. G., Lawrence, J. B., and Livingston, D. M. 1991. Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein. Cell 66:, 1155–64.CrossRefPubMedGoogle Scholar
  44. Fantl, V., Stamp, G., Andrews, A., Rosewell, I., and Dickson, C. 1995. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev 9:, 2364–72.PubMedGoogle Scholar
  45. Fero, M. L., Randel, E., Gurley, K. E., Roberts, J. M., and Kemp, C. J. 1998. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396:, 177–80.PubMedGoogle Scholar
  46. Fero, M. L., Rivkin, M., Tasch, M., Porter, P., Carow, C. E., Firpo, E., Polyak, K., Tsai, L. H., Broudy, V., Perlmutter, R. M., Kaushansky, K., and Roberts, J. M. 1996, A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85:, 733–44.CrossRefPubMedGoogle Scholar
  47. Field, S. J., Tsai, F. Y., Kuo, F., Zubiaga, A. M., Kaelin, W. G., Livingston, D. M., Orkin, S. H., and Greenberg, M. E. 1996. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85:, 549–61.CrossRefPubMedGoogle Scholar
  48. Francke, U., and Kung, F. 1976. Sporadic bilateral retinoblastoma and 13q-chromosomal deletion. Med Pediatr Oncol 2:, 379–85.PubMedGoogle Scholar
  49. Franklin, D. S., Godfrey, V. L., Lee, H., Kovalev, G. I., Schoonhoven, R., Chen-Kiang, S., Su, L., and Xiong, Y. 1998. CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 12:, 2899–911.PubMedGoogle Scholar
  50. Franklin, D. S., Godfrey, V. L., O’Brien, D. A., Deng, C., and Xiong, Y. 2000, Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol 20:, 6147–58.CrossRefPubMedGoogle Scholar
  51. Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., and Dryja, T. P. 1986. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:, 643–6.CrossRefPubMedGoogle Scholar
  52. Fung, Y. K., Murphree, A. L., T’Ang, A., Qian, J., Hinrichs, S. H., and Benedict, W. F. 1987. Structural evidence for the authenticity of the human retinoblastoma gene. Science 236:, 1657–61.PubMedGoogle Scholar
  53. Gaubatz, S., Lindeman, G. J., Ishida, S., Jakoi, L., Nevins, J. R., Livingston, D. M., and Rempel, R. E. 2000. E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol Cell 6: 729–35.CrossRefPubMedGoogle Scholar
  54. Geng, Y., Whoriskey, W., Park, M. Y., Bronson, R. T., Medema, R. H., Li, T., Weinberg, R. A., and Sicinski, P. 1999. Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 97:, 767–77.CrossRefPubMedGoogle Scholar
  55. Geng, Y., Yu, Q., Whoriskey, W., Dick, F., Tsai, K. Y., Ford, H. L., Biswas, D. K., Pardee, A. B., Amati, B., Jacks, T., Richardson, A., Dyson, N., and Sicinski, P. 2001. Expression of cyclins E1 and E2 during mouse development and in neoplasia. Proc Natl Acad Sci U S A 98:, 13138–43.PubMedGoogle Scholar
  56. Girling, R., Partridge, J. F., Bandara, L. R., Burden, N., Totty, N. F., Hsuan, J, J., and La Thangue, N. B. 1993. A new component of the transcription factor DRTF1/E2F. Nature 362:, 83–7.CrossRefPubMedGoogle Scholar
  57. Gu, W., Schneider, J. W., Condorelli, G., Kaushal, S., Mahdavi, V., and Nadal-Ginard, B. 1993. Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell 72:, 309–24.CrossRefPubMedGoogle Scholar
  58. Gu, Y., Turck, C. W., and Morgan, D. O. 1993. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 366:, 707–10.CrossRefPubMedGoogle Scholar
  59. Gudas, J. M., Payton, M., Thukral, S., Chen, E., Bass, M., Robinson, M. O., and Coats, S. 1999. Cyclin E2, a novel G1 cyclin that binds Cdk2 and is aberrantly expressed in human cancers. Mol Cell Biol 19:, 612–22.PubMedGoogle Scholar
  60. Hamel, P. A., Gill, R. M., Phillips, R. A., and Gallie, B. L. 1992, Transcriptional repression of the E2-containing promoters EIIaE, c-myc, and RB1 by the product of the RB1 gene. Mol Cell Biol 12:, 3431–8.PubMedGoogle Scholar
  61. Hannon, G. J., and Beach, D. 1994. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371:, 257–61.CrossRefPubMedGoogle Scholar
  62. Hansen, M. F., Koufos, A., Gallie, B. L., Phillips, R. A., Fodstad, O., Brogger, A., Gedde-Dahl, T., and Cavenee, W. K. 1985. Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Proc Natl Acad Sci U S A 82:, 6216–20.PubMedGoogle Scholar
  63. Harbour, J. W., Lai, S. L., Whang-Peng, J., Gazdar, A. F., Minna, J. D., and Kaye, F. J. 1988. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241:, 353–7.PubMedGoogle Scholar
  64. Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A., and Dean, D. C. 1999. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98:, 859–69.CrossRefPubMedGoogle Scholar
  65. Harrison, D. J., Hooper, M, L., Armstrong, J. F., and Clarke, A. R. 1995. Effects of heterozygosity for the Rb-ltl9neo allele in the mouse. Oncogene 10:, 1615–20.PubMedGoogle Scholar
  66. Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, N., and Mukai, T. 1996. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet 14:, 171–3.CrossRefPubMedGoogle Scholar
  67. Hatakeyama, M., Brill, J. A., Fink, G. R., and Weinberg, R. A. 1994. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev 8:, 1759–71.PubMedGoogle Scholar
  68. Hateboer, G., Kerkhoven, R. M., Shvarts, A., Bernards, R., and Beijersbergen, R. L. 1996. Degradation of E2F by the ubiquitin-proteasome pathway: regulation by retinoblastoma family proteins and adenovirus transforming proteins. Genes Dev 10:, 2960–70.PubMedGoogle Scholar
  69. Helin, K., Holm, K., Niebuhr, A., Eiberg, H., Tommerup, N., Hougaard, S., Poulsen, H. S., Spang-Thomsen, M., and Norgaard, P. 1997. Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinoma. Proc Natl Acad Sci U S A 94:, 6933–8.CrossRefPubMedGoogle Scholar
  70. Hinds, P. W., Mittnacht, S., Dulic, V., Arnold, A., Reed, S. I., and Weinberg, R. A. 1992. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 70:, 993–1006.CrossRefPubMedGoogle Scholar
  71. Hofmann, F., Martelli, F., Livingston, D. M., and Wang, Z., 1996. The retinoblastoma gene product protects E2F-1 from degradation by the ubiquitin-proteasome pathway. Genes Dev 10:, 2949–59.PubMedGoogle Scholar
  72. Holmberg, C., Helin, K., Sehested, M., and Karlstrom, O. 1998. E2F-l-induced p53-independent apoptosis in transgenic mice. Oncogene 17:, 143–55.CrossRefPubMedGoogle Scholar
  73. Horowitz, J. M., Park, S, H., Bogenmann, E., Cheng, J. C., Yandell, D. W., Kaye, F. J., Minna, J. D., Dryja, T. P., and Weinberg, R. A. 1990. Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci U S A 87:, 2775–9.PubMedGoogle Scholar
  74. Hsiao, K. M., McMahon, S. L., and Farnham, P. J. 1994. Multiple DNA elements are required for the growth regulation of the mouse E2F1 promoter. Genes Dev 8:, 1526–37.PubMedGoogle Scholar
  75. Hsieh, J, K., Fredersdorf, S., Kouzarides, T., Martin, K., and Lu, X. 1997. E2F1-induced apoptosis requires DNA binding but not transactivation and is inhibited by the retinoblastoma protein through direct interaction. Genes Dev 11:, 1840–52.PubMedGoogle Scholar
  76. Hu, N., Gutsmann, A., Herbert, D.C., Bradley, A., Lee, W. H., and Lee, E. Y. 1994. Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9:, 1021–7.PubMedGoogle Scholar
  77. Huang, H. J., Yee, J. K., Shew, J. Y., Chen, P. L., Bookstein, R., Friedmann, T., Lee, E. Y., and Lee, W. H. 1988. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science 242:, 1563–6.PubMedGoogle Scholar
  78. Humbert, P. O., Rogers, C., Ganiatsas, S., Landsberg, R. L., Trimarchi, J. M., Dandapani, S., Brugnara, C., Erdman, S., Schrenzel, M., Bronson, R. T., and Lees, J. A. 2000. E2F4 is essential for normal erythrocyte maturation and neonatal viability. Mol Cell 6:, 281–91.CrossRefPubMedGoogle Scholar
  79. Humbert, P. O., Verona, R., Trimarchi, J. M., Rogers, C., Dandapani, S., and Lees, J. A. 2000. E2f3 is critical for normal cellular proliferation. Genes Dev 14:, 690–703.PubMedGoogle Scholar
  80. Ichimur, K., Hanafusa, H., Takimoto H., Ohgama, Y., Akagi, T., and Shimizu, K. 2000 Structure of the human retinoblastoma-related p107 gene and its intragenic deletion in a B-cell lymphma cell line. Gene 251:37–43.Google Scholar
  81. Imanishi, Y., Hosokawa, Y., Yoshimoto, K., Schipani, E., Mallya, S., Papanikolaou, A., Kifor, O., Tokura, T., Sablosky, M., Ledgard, F., Gronowicz, G., Wang, T. C., Schmidt, E. V., Hall, C., Brown, E. M., Bronson, R., and Arnold, A. 2001. Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest 107:, 1093–102.PubMedGoogle Scholar
  82. Ishida, S., Huang, E., Zuzan, H., Spang, R., Leone, G., West, M., and Nevins, J. R. 2001. Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol Cell Biol 21:, 4684–99.CrossRefPubMedGoogle Scholar
  83. Jacks, T., Fazeli, A., Schmitt, E. M., Bronson, R. T., Goodell, M. A., and Weinberg, R. A. 1992. Effects of an Rb mutation in the mouse. Nature 359:, 295–300.CrossRefPubMedGoogle Scholar
  84. Jiang, Z., and Zacksenhaus, E. 2002. Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma. J Cell Biol 156:, 185–98.CrossRefPubMedGoogle Scholar
  85. Johnson, D. G., Ohtani, K., and Nevins, J. R. 1994. Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev 8:, 1514–25.PubMedGoogle Scholar
  86. Johnson, D. G., Schwarz, J. K., Cress, W. D., and Nevins, J. R. 1993. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 365:, 349–52.CrossRefPubMedGoogle Scholar
  87. Kalma, Y., Marash, L., Lamed, Y., and Ginsberg, D. 2001 Mar 15. Expression analysis using DNA microarrays demonstrates that E2F-1 up-regulates expression of DNA replication genes including replication protein A2. Oncogene 20:, 1379–87.CrossRefPubMedGoogle Scholar
  88. Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigtan, S. V., Stockert, E., Day, R. S. r., Johnson, B. E., and Skolnick, M. H. 1994. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:, 436–40.PubMedGoogle Scholar
  89. 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:, 649–59.CrossRefPubMedGoogle Scholar
  90. Karsunky, H., Geisen, C., Schmidt, T., Haas, K., Zevnik, B., Gau, E., and Moroy, T. 1999. Oncogenic potential of cyclin E in T-cell lymphomagenesis in transgenicmice: evidence for cooperation between cyclin E and Ras but not Myc. Oncogene 18:, 7816–24.PubMedGoogle Scholar
  91. Kato, J., Matsushime, H., Hiebert, S. W., Ewen, M. E., and Sherr, C. J. 1993. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 7:, 331–42.PubMedGoogle Scholar
  92. Keyomarsi, K., O’Leary, N., Molnar, G., Lees, E., Fingert, H. J., and Pardee, A. B. 1994. Cyclin E, a potential prognostic marker for breast cancer. Cancer Res 54:, 380–5.PubMedGoogle Scholar
  93. Khatib, Z. A., Matsushime, H., Valentine, M., Shapiro, D. N., Sherr, C. J., and Look, A. T. 1993. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res 53:, 5535–41.PubMedGoogle Scholar
  94. Kim, H. Y., Ahn, B. Y., and Cho, Y. 2001. Structural basis for the inactivation of retinoblastoma tumor suppressor by SV40 large T antigen. Embo J 20:, 295–304.PubMedGoogle Scholar
  95. Kiyokawa, H., Kineman, R. D., Manova-Todorova, K. O., Scares, V. C., Hoffman, E. S., Ono, M., Khanam, D., Hayday, A. C., Frohman, L. A., and Koff, A. 1996. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kipl). Cell 85:, 721–32.CrossRefPubMedGoogle Scholar
  96. Knudson, A. G., Jr. 1971. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68:, 820–3.PubMedGoogle Scholar
  97. Knudson, A. G., Jr., Meadows, A. T., Nichols, W. W., and Hill, R. 1976. Chromosomal deletion and retinoblastoma. N Engl J Med 295:, 1120–3.PubMedGoogle Scholar
  98. Kovesdi, I., Reichel, R., and Nevins, J. R. 1986. Identification of a cellular transcription factor involved in E1A trans-activation. Cell 45:, 219–28.CrossRefPubMedGoogle Scholar
  99. Kowalik, T. F., DeGregori, J., Schwarz, J. K., and Nevins, J. R. 1995. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol 69:, 2491–500.PubMedGoogle Scholar
  100. Krek, W., Ewen, M. E., Shirodkar, S., Arany, Z., Kaelin, W. G., Jr., and Livingston, D. M. 1994. Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 78:, 161–72.CrossRefPubMedGoogle Scholar
  101. Krek, W., Xu, G., and Livingston, D. M. 1995. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Cell 83:, 1149–58.CrossRefPubMedGoogle Scholar
  102. Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A., and Berns, A. 2001. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413:, 83–6.CrossRefPubMedGoogle Scholar
  103. La Thangue, N. B., and Rigby, P. W. 1987. An adenovirus E1A-like transcriptionfactor is regulated during the differentiation of murine embryonal carcinoma stem cells. Cell 49:, 507–13.PubMedGoogle Scholar
  104. LaBaer, J., Garrett, M. D., Stevenson, L. F., Slingerland, J. M., Sandhu, C., Chou, H. S., Fattaey, A., and Harlow, E. 1997. New functional activities for the p21 family of CDK inhibitors. Genes Dev 11:, 847–62.Google Scholar
  105. Lai, A., Kennedy, B. K., Barbie, D. A., Bertos, N. R., Yang, X. J., Theberge, M. C., Tsai, S. C., Seto, E., Zhang, Y., Kuzmichev, A., Lane, W. S., Reinberg, D., Harlow, E., and Branton, P. E. 2001. RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest. Mol Cell Biol 21:, 2918–32.PubMedGoogle Scholar
  106. Lai, A., Lee, J. M., Yang, W. M., DeCaprio, J. A., Kaelin, W. G., Jr., Seto, E., and Branton, P. E. 1999. RBP1 recruits both histone deacetylase-dependent and-independent repression activities to retinoblastoma family proteins. Mol Cell Biol 19:, 6632–41.PubMedGoogle Scholar
  107. Lam, E. W., and Watson, R. J. 1993. An E2F-binding site mediates cell-cycle regulated repression of mouse B-myb transcription. Embo J 12:, 2705–13.PubMedGoogle Scholar
  108. Lasorella, A., Noseda, M., Beyna, M., Yokota, Y., and Iavarone, A. 2000. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407:, 592–8.PubMedGoogle Scholar
  109. Latres, E., Malumbres, M., Sotillo, R., Martin, J., Ortega, S., Martin-Caballero, J., Flores, J. M., Cordon-Cardo, C., and Barbacid, M. 2000. Limited overlapping roles of P15(INK4b) and P18(INK4c) cell cycle inhibitors in proliferation and tumorigenesis. Embo J 19:, 3496–506.CrossRefPubMedGoogle Scholar
  110. LeCouter, J. E., Kablar, B., Hardy, W. R., Ying, C., Megeney, L. A., May, L. L., and Rudnicki, M. A. 1998. Strain-dependent myeloid hyperplasia, growth deficiency, and accelerated cell cycle in mice lacking the Rb-related p107 gene. Mol Cell Biol 18:, 7455–65.Google Scholar
  111. LeCouter, J. E., Kablar, B., Whyte, P. F., Ying, C., and Rudnicki, M. A. 1998. Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene. Development 125:, 4669–79.Google Scholar
  112. Lee, E, Y., Chang, C. Y., Hu, N., Wang, Y. C., Lai, C. C., Herrup, K., Lee, W. H., and Bradley, A. 1992. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359:, 288–94.CrossRefPubMedGoogle Scholar
  113. Lee, E. Y., To, H., Shew, J. Y., Bookstein, R., Scully, P., and Lee, W. H. 1988. Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 241:, 218–21.PubMedGoogle Scholar
  114. Lee, J. O., Russo, A, A., and Pavletieh, N. P. 1998. Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7. Nature 391:, 859–65.PubMedGoogle Scholar
  115. Lee, M. H., Williams, B. O., Mulligan, G., Mukai, S., Bronson, R. T., Dyson, N., Harlow, E., and Jacks, T. 1996, Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev 10:, 1621–32.PubMedGoogle Scholar
  116. Lee, W. H., Bookstein, R., Hong, F., Young, L. J., Shew, J. Y., and Lee, E. Y. 1987. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235:, 1394–9.PubMedGoogle Scholar
  117. Leone, G., DeGregori, J., Yan, Z., Jakoi, L., Ishida, S., Williams, R. S., and Nevins, J. R. 1998. E2F3 activity is regulated during the cell cycle and is required for the induction of S phase. Genes Dev 12:, 2120–30PubMedGoogle Scholar
  118. Li, Y., Graham, C., Lacy, S., Duncan, A. M., and Whyte, P. 1993. The adenovirus ElA-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Dev 7:, 2366–77.PubMedGoogle Scholar
  119. Lin, W. C., Lin, F, T., and Nevins, J. R. 2001. Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev 15:, 1833–44.PubMedGoogle Scholar
  120. Lindeman, G. J., Dagnino, L., Gaubatz, S., Xu, Y., Bronson, R. T., Warren, H. B., and Livingston, D. M. 1998. A specific, nonproliferative role for E2F-5 in choroid plexus function revealed by gene targeting. Genes Dev 12:, 1092–8.PubMedGoogle Scholar
  121. Livingston, D. M., Kaelin, W., Chittenden, T., and Qin, X. 1993. Structural and functional contributions to the G1 blocking action of the retinoblastoma protein, (the 1992 Gordon Hamilton Fairley Memorial Lecture). Br J Cancer 68:, 264–8.PubMedGoogle Scholar
  122. Loda, M., Cukor, B., Tam, S. W., Lavin, P., Fiorentino, M., Draetta, G. F., Jessup, J. M., and Pagano, M. 1997. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3:, 231–4.CrossRefPubMedGoogle Scholar
  123. Ludlow, J. W., DeCaprio, J. A., Huang, C. M., Lee, W. H., Paucha, E., and Livingston, D. M. 1989. SV40 large T antigen bind spreferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family. Cell 56:, 57–65.CrossRefPubMedGoogle Scholar
  124. Luo, R. X., Postigo, A. A., and Dean, D. C. 1998. Rb interacts with histone deacetylase to repress transcription. Cell 92:, 463–73.CrossRefPubMedGoogle Scholar
  125. Ma, Y., Croxton, R., Moorer, R. L., Jr., and Cress, W. D. 2002. Identification of novel E2F1-regulated genes by microarray. Arch Biochem Biophys 399:, 212–24.CrossRefPubMedGoogle Scholar
  126. Maandag, E. C., van der Valk, M., Vlaar, M., Feltkamp, C., O’Brien, J., van Roon, M., van der Lugt, N., Berns, A., and te Riele, H. 1994. Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. Embo J 13:, 4260–8.PubMedGoogle Scholar
  127. Magnaghi-Jaulin, L., Groisman, R., Naguibneva, I., Robin, P., Lorain, S., Le Villain, J. P., Troalen, F., Trouche, D., and Harel-Bellan, A. 1998. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391:, 601–5.PubMedGoogle Scholar
  128. Marti, A., Wirbelauer, C., Scheffner, M., and Krek, W. 1999. Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation. Nat Cell Biol 1:, 14–9.PubMedGoogle Scholar
  129. Martinez-Balbas, M. A., Bauer, U. M., Nielsen, S. J., Brehm, A., and Kouzarides, T. 2000. Regulation of E2F1 activity by acetylation. Embo J. 19:, 662–71.CrossRefPubMedGoogle Scholar
  130. Marzio, G., Wagener, C., Gutierrez, M. I., Cartwright, P., Helin, K., and Giacca, M. 2000. E2F family members are differentially regulated by reversible acetylation. J Biol Chem 275:, 10887–92.CrossRefPubMedGoogle Scholar
  131. Maser, R. S., Mirzoeva, O. K,, Wells, J., Olivares, H., Williams, B. R., Zinkel, R. A., Farnham, P. J., and Petrini, J. H. 2001. Mre11 complex and DNA replication: linkage to E2F and sites of DNA synthesis. Mol Cell Biol 21:, 6006–16.CrossRefPubMedGoogle Scholar
  132. Matsuoka, S., Thompson, J. S., Edwards, M. C., Bartletta, J. M., Grundy, P., Kalikin, L. M., Harper, J. W., Elledge, S. J., and Feinberg, A. P. 1996. Imprinting of the gene encoding a human cyclindependent kinase inhibitor, p57KIP2, on chromosome 11pl5. Proc Natl Acad Sci U S A 93:, 3026–30.CrossRefPubMedGoogle Scholar
  133. Mayol, X., Grana, X., Baldi, A., Sang, N., Hu, Q., and Giordano, A. 1993. Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogens 8:, 2561–6.Google Scholar
  134. Mihara, K., Cao, X. R., Yen, A., Chandler, S., Driscoll, B., Murphree, A. L., T’Ang, A., and Fung, Y. K. 1989. Cell cycle-dependent regulation of phosphorylation of the human retinoblastoma gene product. Science 246:, 1300–3.PubMedGoogle Scholar
  135. Moberg, K. H., Bell, D. W., Wahrer, D. C., Haber, D. A., and Hariharan, I. K. 2001. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413:, 311–6.CrossRefPubMedGoogle Scholar
  136. Moons, D. S., Jirawatnotai, S., Tsutsui, T., Franks, R., Parlow, A. F., Hales, D. B., Gibori, G., Fazleabas, A. T., and Kiyokawa, H. 2002. Intact follicular maturation and defective luteal function in mice deficient for cyclin-dependent kinase-4. Endocrinology 143:, 647–54.PubMedGoogle Scholar
  137. Morris, E. J., and Dyson, N. J. 2001. Retinoblastoma protein partners. Adv Cancer Res 82:, 1–54.PubMedGoogle Scholar
  138. Muller, H., Bracken, A. P., Vernell, R., Moroni, M. C., Christians, F., Grassilli, E., Prosperini, E., Vigo, E., Oliner, J. D., and Helin, K. 2001. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev 15:, 267–85.CrossRefPubMedGoogle Scholar
  139. Muller, H., Moroni, M. C, Vigo, E., Petersen, B. O., Bartek, J., and Helin, K. 1997. Induction of S-phase entry by E2F transcription factors depends on their nuclearlocalization. Mol Cell Biol 17:, 5508–20.PubMedGoogle Scholar
  140. Munger, K., Werness, B. A., Dyson, N., Phelps, W, C., Harlow, E,, and Howley, P. M. 1989. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumorsuppressor gene product, Embo J 8:, 4099–105.PubMedGoogle Scholar
  141. Nakayama, K., Ishida, N., Shirane, M., Inomata, A., Inoue, T., Shishido, N., Horii, I., Loh, D. Y., and Nakayama, K. 1996. Micelacking p27 (Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85:, 707–20.CrossRefPubMedGoogle Scholar
  142. Nicolas, E., Morales, V., Magnaghi-Jaulin, L., Harel-Bellan, A., Richard-Foy, H., and Trouche, D. 2000. RbAp48 belongs to the histone deacetylase complex that associates with the retinoblastoma protein. J Biol Chem 275:, 9797–804.PubMedGoogle Scholar
  143. Nielsen, N. H., Arnerlov, C., Emdin, S. O., and Landberg, G. 1996. Cyclin E overexpression, a negative prognostic factor in breast cancer with strong correlation to oestrogen receptor status. Br J Cancer 74:, 874–80.PubMedGoogle Scholar
  144. Nielsen, S. J., Schneider, R., Bauer, U. M., Bannister, A. J., Morrison, A., O’Carroll, D., Firestein, R., Cleary, M., Jenuwein, T., Herrera, R. E., and Kouzarides, T. 2001. Rb targetshistone H3 methylation and HP1 to promoters. Nature 412:, 561–5.CrossRefPubMedGoogle Scholar
  145. Nikitin, A. Y., Juarez-Perez, M. I., Li, S., Huang, L., and Lee, W. H. 1999. RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/-mice. Proc Natl Acad Sci U S A 96:, 3916–21.CrossRefPubMedGoogle Scholar
  146. Nip, J., Strom, D. K., Fee, B. E., Zambetti, G., Cleveland, J. L., and Hiebert, S. W. 1997. E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis. Mol Cell Biol 17:, 1049–56.PubMedGoogle Scholar
  147. Noda, A., Ning, Y., Venable, S. F,, Pereira-Smith, O. M., and Smith, J. R. 1994. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211:, 90–8.CrossRefPubMedGoogle Scholar
  148. Ohtani, N., Zebedee, Z., Huot, T. J., Stinson, J. A., Sugimoto, M., Ohashi, Y., Sharrocks, A. D., Peters, G., and Hara, E. 2001. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409:, 1067–70.CrossRefPubMedGoogle Scholar
  149. Pagano, M., Tam, S. W., Theodoras, A. M., Beer-Romero, P., Del Sal, G., Chau, V., Yew, P. R., Draetta, G. F., and Rolfe, M. 1995. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269:, 682–5.PubMedGoogle Scholar
  150. Palmero, I., McConnell, B., Parry, D., Brookes, S., Hara, E., Bates, S., Jat, P., and Peters, G. 1997. Accumulation of p16INK4a in mousefibroblasts as a function of replicative senescence and not of retinoblastoma gene status. Oncogene 15:, 495–503.CrossRefPubMedGoogle Scholar
  151. Pardee, A. B. 1974. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A 71:, 1286–90.PubMedGoogle Scholar
  152. Park, M. S., Rosai, J., Nguyen, H. T., Capodieci, P., Cordon-Cardo, C., and Koff, A, 1999. p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice. Proc Natl Acad Sci U S A 96:, 6382–7.PubMedGoogle Scholar
  153. Peeper, D. S., Dannenberg, J. H., Douma, S., te Riele, H., and Bernards, R. 2001. Escape from premature senescence is not sufficient for oncogenic transformation by Ras, Nat Cell Biol 3:, 198–203.CrossRefPubMedGoogle Scholar
  154. Peters, G. 1994. The D-type cyclins and their role in tumorigenesis, J Cell Sci Suppl 18:, 89–96.PubMedGoogle Scholar
  155. Phillips, A. C., Bates, S., Ryan, K. M., Helin, K., and Vousden, K. H. 1997. Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev 11:, 1853–63.PubMedGoogle Scholar
  156. Pierce, A. M., Gimenez-Conti, I. B., Schneider-Broussard, R., Martinez, L. A., Conti, C. J., and Johnson, D. G. 1998. Increased E2F1 activity induces skin tumors in mice heterozygous and nullizygous for p53. Proc Natl Acad Sci U S A 95:, 8858–63.CrossRefPubMedGoogle Scholar
  157. Polyak, K., Lee, M. H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P., and Massague, J. 1994. Cloning of p27Kipl, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78:, 59–66.CrossRefPubMedGoogle Scholar
  158. Qian, Y. W., and Lee, E. Y. 1995. Dual retinoblastoma-binding proteins with properties related to a negative regulator of ras in yeast. J Biol Chem 270:, 25507–13.PubMedGoogle Scholar
  159. Qin, X. Q., Livingston, D. M., Ewen, M., Sellers, W. R., Arany, Z., and Kaelin, W. G., Jr. 1995. The transcription factor E2F-1 is a downstream target of RB action. Mol Cell Biol 15:, 742–55.PubMedGoogle Scholar
  160. Rane, S. G., Cosenza, S. C., Mettus, R. V., and Reddy, E. P. 2002. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol 22:, 644–56.CrossRefPubMedGoogle Scholar
  161. Rane, S. G., Dubus, P., Mettus, R. V., Galbreath, E. J., Boden, G., Reddy, E. P., and Barbacid, M. 1999. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22:, 44–52.PubMedGoogle Scholar
  162. Rempel, R. E., Saenz-Robles, M. T., Storms, R., Morham, S., Ishida, S., Engel, A., Jakoi, L., Melhem, M. P., Pipas, J. M., Smith, C., and Nevins, J. R. 2000. Loss of E2F4 activity leads to abnormal development of multiple cellular lineages. Mol Cell 6:, 293–306.CrossRefPubMedGoogle Scholar
  163. Reynisdottir, I., Polyak, K., Lavarone, A., and Massague, J. 1995. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev 9:, 1831–45.PubMedGoogle Scholar
  164. Robanus-Maandag, E., Dekker, M., van der Valk, M., Carrozza, M. L., Jeanny, J. C., Dannenberg, J. H., Berns, A., and te Riele, H. 1998. p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev 12:, 1599–609.PubMedGoogle Scholar
  165. Ruas, M., and Peters, G. 1998. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1378:, Fl15–77.Google Scholar
  166. Rubin, E., Mittnacht, S., Villa-Moruzzi, E., and Ludlow, J. W. 2001. Site-specific and temporally-regulated retinoblastoma protein dephosphorylation by protein phosphatase type 1. Oncogene 20:, 3776–85.CrossRefPubMedGoogle Scholar
  167. Russell, J. L., Powers, J. T., Rounbehler, R. J., Rogers, P. M., Conti, C. J., and Johnson, D. G. 2002, ARF Differentially Modulates Apoptosis Induced by E2F1 and Myc. Mol. Cell Biol. 22:, 1360–8.PubMedGoogle Scholar
  168. Sage, J., Mulligan, G. J., Attardi, L. D., Miller, A., Chen, S., Williams, B., Theodorou, E., and Jacks, T. 2000. Targeted disruption of the three Rb-related genes leads to loss of G(l) control and immortalization. Genes Dev 14:, 3037–50.CrossRefPubMedGoogle Scholar
  169. Schmidt, E. E., Ichimura, K., Reifenberger, G., and Collins, V. P. 1994. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 54:, 6321–4.PubMedGoogle Scholar
  170. Schwab, M., and Tyers, M. 2001. Cell cycle. Archipelago of destruction. Nature 413:, 268–9.CrossRefPubMedGoogle Scholar
  171. Sears, R., Ohtani, K., and Nevins, J. R. 1997. Identification of positively and negatively acting elements regulating expression of the E2F2 gene in response to cell growth signals. Mol Cell Biol 17:, 5227–35.PubMedGoogle Scholar
  172. Sellers, W. R., Novitch, B. G., Miyake, S., Heith, A., Otterson, G. A., Kaye, F, J., Lassar, A. B., and Kaelin, W. G., Jr. 1998. Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth. Genes Dev 12:, 95–106.PubMedGoogle Scholar
  173. Seoane, J., Pouponnot, C., Staller, P., Schader, M., Eilers, M., and Massague, J. 2001. TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol 3:, 400–8.CrossRefPubMedGoogle Scholar
  174. Serrano, M., Lee, H., 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.CrossRefPubMedGoogle Scholar
  175. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., and Lowe, S. W. 1997. Oncogenic ras provokes prematurecell senescence associated with accumulation of p53 and p16INK4a. Cell 88:, 593–602.CrossRefPubMedGoogle Scholar
  176. Shan, B., and Lee, W. H., 1994. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol Cell Biol 14:, 8166–73.PubMedGoogle Scholar
  177. Sharpless, N. E., Bardeesy, N., Lee, K. H., Carrasco, D., Castrillon, D. H., Aguirre, A. J., Wu, E. A., Horner, J. W., and DePinho, R. A. 2001. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413:, 86–91.CrossRefPubMedGoogle Scholar
  178. Sherr, C. J. 1996. Cancer cell cycles. Science 274:, 1672–7.CrossRefPubMedGoogle Scholar
  179. Sherr, C. J. 2001. Parsing Ink4a/Arf: “pure” pl6-null mice. Cell 106:, 531–4.CrossRefPubMedGoogle Scholar
  180. Sherr, C. J. 2000. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 60:, 3689–95.PubMedGoogle Scholar
  181. Sicinski, P., Donaher, J. L., Geng, Y., Parker, S. B., Gardner, H., Park, M. Y., Robker, R. L., Richards, J. S., McGinnis, L. K., Biggers, J. D., Eppig, J. J., Branson, R. T., Elledge, S. J., and Weinberg, R. A. 1996. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384:, 470–4.CrossRefPubMedGoogle Scholar
  182. Sicinski, P., Donaher, J. L., Parker, S. B., Li, T., Fazeli, A., Gardner, H., Haslam, S. Z., Bronson, R. T., Elledge, S. J., and Weinberg, R. A. 1995. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:, 621–30.CrossRefPubMedGoogle Scholar
  183. Slansky, J. E., Li, Y., Kaelin, W. G., and Farnham, P. J. 1993. A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter. Mol Cell Biol 13:, 1610–8.PubMedGoogle Scholar
  184. Sotillo, R., Dubus, P., Martin, J., de la Cueva, E., Ortega, S., Malumbres, M., and Barbacid, M. 2001. Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. Embo J. 20:, 6637–47.CrossRefPubMedGoogle Scholar
  185. Staller, P., Peukert, K., Kiermaier, A., Seoane, J., Lukas, J., Karsunky, H., Moroy, T., Bartek, J., Massague, J., Hanel, F., and Eilers, M. Cell Biol 2001 Apr. Repression of p15INK4b expression by Myc through association with Miz-1. Nat 3:, 392–9.Google Scholar
  186. Strobeck, M. W., Knudsen, K. E., Fribourg, A. F., DeCristofaro, M. F., Weissman, B. E., Imbalzano, A. N., and Knudsen, E. S. 2000. BRG-1 is required for RB-mediated cell cycle arrest. Proc Natl Acad Sci U S A 97:, 7748–53.CrossRefPubMedGoogle Scholar
  187. Strohmaier, H., Spruck, C. H., Kaiser, P., Won, K. A., Sangfelt, O., and Reed, S. I. 2001. HumanF-box protein hCdc4 targets cyclin E for proteolysis andis mutated in abreast cancercellline. Nature 413:, 316–22.CrossRefPubMedGoogle Scholar
  188. Sumegi, J., Uzvolgyi, E., and Klein, G. 1990. Expression of the RB gene under the control of MuLV-LTR suppresses tumorigenicity of WERI-Rb-27 retinoblastoma cells in immunodefective mice. Cell Growth Differ 1:, 247–50.PubMedGoogle Scholar
  189. T’Ang, A., Varley, J.M., Chakraborty, S., Murphree, A.L., and Fung, Y. K. 1988. Structural rearrangement of the retinoblastoma gene in human breast carcinoma. Science 242:, 263–6.PubMedGoogle Scholar
  190. Takahashi, R., Hashimoto, T., Xu, H. J., Hu, S. X., Matsui, T., Miki, T., Bigo-Marshall, H., Aaronson, S. A., and Benedict, W. F. 1991. The retinoblastoma gene functions as a growth and tumor suppressor in human bladder carcinoma cells. Proc Natl Acad Sci U S A 88:, 5237–61.Google Scholar
  191. Tokitou, F., Nomura, T., Khan, M. M., Kaul, S. C., Wadhwa, R., Yasukawa, T., Kohno, I., and Ishii, S. 1999. Viral ski inhibits retinoblastoma protein (Rb)-mediatedtranscriptional repression in a dominant negative fashion. J Biol Chem 274:, 4485–8.CrossRefPubMedGoogle Scholar
  192. Trimarchi, J. M., and Lees, J. A. 2002. Sibling rivalry in the E2F family. Nat. Rev. Mol. Cell. Biol. 3:, 11–20.CrossRefPubMedGoogle Scholar
  193. Trouche, D., Le Chalony, C., Muchardt, C., Yaniv, M., and Kouzarides, T. 1997. RB and hbrm cooperate to repress the activation functions of E2F1. Proc Natl Acad Sci U S A 94:, 11268–73.CrossRefPubMedGoogle Scholar
  194. Tsai, K. Y., Hu, Y., Macleod, K. F., Crowley, D., Yamasaki, L., and Jacks, T. 1998. Mutation of E2f-l suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell 2:, 293–304.CrossRefPubMedGoogle Scholar
  195. Tsai, K. Y., MacPherson, D., Rubinson, D. A., Crowley, D., and Jacks, T. 2002. ARF is not required for apoptosis in Rb mutant mouse embryos. Curr Biol 12:, 159–63.PubMedGoogle Scholar
  196. Tsutsui, T., Hesabi, B., Moons, D. S., Pandolfi, P. P., Hansel, K. S., Koff, A., and Kiyokawa, H. 1999. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kipl) activity. Mol Cell Biol 19:, 7011–9.PubMedGoogle Scholar
  197. Vandel, L., Nicolas, E., Vaute, O., Ferreira, R., Ait-Si-Ali, S., and Trouche, D. 2001. Transcriptional repression by the retinoblastoma protein through the recruitment of a histone methyltransferase. Mol Cell Biol 21:, 6484–94.CrossRefPubMedGoogle Scholar
  198. Verona, R., Moberg, K., Estes, S., Starz, M., Vernon, J. P., and Lees, J. A. 1997. E2F activity is regulated by cell cycle-dependent changes in subcellular localization. Mol Cell Biol 17:, 7268–82.PubMedGoogle Scholar
  199. Wang, C. Y., Petryniak, B., Thompson, C. B., Kaelin, W. G., and Leiden, J. M. 1993. Regulation of the Ets-related transcription factor E1f-1 by binding to the retinoblastoma protein. Science 260:, 1330–5.PubMedGoogle Scholar
  200. Wang, T. C., Cardiff, R. D., Zukerberg, L., Lees, E., Arnold, A., and Schmidt, E. V. 1994. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369:, 669–71.PubMedGoogle Scholar
  201. Weber, J. D., Jeffers, J. R., Rehg, J. E., Randle, D. H., Lozano, G., Roussel, M. F., Shew C. J., and Zambetti, G. P. 2000. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev 14:, 2358–65.CrossRefPubMedGoogle Scholar
  202. Weinmann, A. S., Yan, P. S., Oberley, M. J., Huang, T. H., and Farnham, P. J. 2002. Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes Dev 16:, 235–44.CrossRefPubMedGoogle Scholar
  203. Weintraub, S. J., Prater, C. A., and Dean, D. C. 1992. Retinoblastoma protein switches the E2F site from positive to negative element. Nature 358:, 259–61.CrossRefPubMedGoogle Scholar
  204. Wells, J., Graveel, C. R., Bartley, S. M., Madore, S. J., and Farnham, P. J. 2002. The identification of E2Fl-specific target genes. Proc Natl Acad Sci U S A 99:, 3890–5.CrossRefPubMedGoogle Scholar
  205. Whyte, P., Buchkovich, K. J., Horowitz, J. M., Friend, S. H., Raybuck, M., Weinberg, R. A., and Harlow, E. 1988. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 334:, 124–9.CrossRefPubMedGoogle Scholar
  206. Williams, B. O., Remington, L., Albert, D. M., Mukai, S., Branson, R. T., and Jacks, T. 1994. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet 7:, 480–4.CrossRefPubMedGoogle Scholar
  207. Williams, B. O., Schmitt, E. M., Remington, L., Bronson, R. T., Albert, D. M., Weinberg, R. A., and Jacks, T. 1994. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. Embo J 13:, 4251–9.PubMedGoogle Scholar
  208. Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., Klehmann-Hieb, E., De Plaen, E., Hankeln, T., Meyer zum Buschenfelde, K. H., and Beach, D. 1995. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269:, 1281–4.PubMedGoogle Scholar
  209. Wu, L., Timmers, C., Maiti, B., Saavedra, H. I., Sang, L., Chong, G. T., Nuckolls, F., Giangrande, P., Wright, F. A., Field, S. J., Greenberg, M. E., Orkin, S., Nevins, J. R., Robinson, M. L., and Leone, G. 2001. The E2F1-3 transcription factors are essential for cellular proliferation. Nature 414:, 457–62.CrossRefPubMedGoogle Scholar
  210. Wu, X., and Levine, A. J. 1994. p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci U S A 91:, 3602–6.PubMedGoogle Scholar
  211. Xiong, Y., Hannon, G. J., Zhang, H., Casso, D., Kobayashi, R., and Beach, D. 1993. p21 is a universal inhibitor of cyclin kinases, Nature 366:, 701–4.CrossRefPubMedGoogle Scholar
  212. Xu, M., Sheppard, K. A., Peng, C. Y., Yee, A. S., and Piwnica-Worms, H. 1994. Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation. Mol Cell Biol 14:, 8420–31.PubMedGoogle Scholar
  213. Yamasaki, L., Bronson, R., Williams, B. O., Dyson, N. J., Harlow, E., and Jacks, T. 1998. Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rbl(+/-)mice. Nat Genet 18:, 360–4.CrossRefPubMedGoogle Scholar
  214. Yamasaki, L., Jacks, T., Bronson, R., Goillot, E., Harlow, E., and Dyson, N. J. 1996. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85:, 537–48.CrossRefPubMedGoogle Scholar
  215. Yang, H., Williams, B. O., Hinds, P. W., Shin, T. S., Jacks, T., Bronson, R. T., and Livingston, D. M. 2002. Tumor suppression by a severely truncated species of retinoblastoma protein. Mol Cell Biol 22:, 3103–10.PubMedGoogle Scholar
  216. Yee, A. S., Reichel, R., Kovesdi, I., and Nevins, J. R. 1987. Promoter interaction of the ElA-inducible factor E2F and its potential role in the formation of a multi-component complex. Embo J 6:, 2061–8.PubMedGoogle Scholar
  217. Zacksenhaus, E., Jiang, Z., Chung, D., Marth, J. D., Phillips, R. A., and Gallie, B. L. 1996. pRb controls proliferation, differentiation, and death of skeletal muscle cells and other lineages during embryogenesis. Genes Dev 10:, 3051–64.PubMedGoogle Scholar
  218. Zarkowska, T., and Mittnacht, S. 1997. Differential phosphorylation of the retinoblastoma protein by G1/S cyclin-dependent kinases. J Biol Chem 272:, 12738–46.CrossRefPubMedGoogle Scholar
  219. Zhang, H. S., Gavin, M., Dahiya, A., Postigo, A. A., Ma, D., Luo, R. X., Harbour, J. W., and Dean, D. C. 2000. Exit from G1 and S phase of the cell cycle is regulated by represser complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 101:, 79–89.CrossRefPubMedGoogle Scholar
  220. Zhang, P., Liegeois, N. J., Wong, C., Finegold, M., Hou, H., Thompson, J. C., Silverman, A., Harper, J. W., DePinho, R. A., and Elledge, S. J. 1997. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 387:, 151–8.PubMedGoogle Scholar
  221. Zheng, N., Fraenkel, E., Pabo, C. O., and Pavletich, N. P. 1999. Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. Genes Dev 13:, 666–74.PubMedGoogle Scholar
  222. Zhu, J. W., Field, S. J., Gore, L., Thompson, M., Yang, H., Fujiwara, Y., Cardiff, R. D., Greenberg, M., Orkin, S. H., and DeGregori, J. 2001. E2F1 and E2F2 determine thresholds for antigen-induced T-cell proliferation and suppress tumorigenesis. Mol Cell Biol 21:, 8547–64.PubMedGoogle Scholar
  223. Zhu, L., Enders, G., Lees, J. A., Beijersbergen, R. L., Bernards, R., and Harlow, E. 1995. The pRB-related protein p107 contains two growth suppression domains: independent interactions with E2F and cyclin/cdk complexes. Embo J 14:, 1904–13.PubMedGoogle Scholar
  224. Zhu, L., van den Heuvel, S., Helin, K., Fattaey, A., Ewen, M., Livingston, D., Dyson, N., and Harlow, E. 1993. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. Genes Dev 7:, 1111–25.PubMedGoogle Scholar
  225. Ziebold, U., Reza, T., Caron, A., and Lees, J. A. 2001. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev. 15:, 386–91.CrossRefPubMedGoogle Scholar
  226. Zindy, F., den Besten, W., Chen, B., Rehg, J. E., Latres, E., Barbacid, M., Pollard, J. W., Sherr, C. J., Cohen, P. E., and Roussel, M. F. 2001. Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18(Ink4c) and p19(Ink4d). Mol Cell Biol 21:, 3244–55.CrossRefPubMedGoogle Scholar
  227. Zindy, F., Scares, H., Herzog, K. H., Morgan, J., Sherr, C. J., and Roussel, M. F. 1997. Expression of INK4 inhibitors of cyclin D-dependent kinases during mouse brain development. Cell Growth Differ 8:, 1139–50.PubMedGoogle Scholar
  228. Zindy, F., van Deursen, J., Grosveld, G., Sherr, C. J., and Roussel, M. F. 2000. INK4d-deficient mice are fertile despite testicular atrophy. Mol Cell Biol 20:, 372–8.PubMedGoogle Scholar
  229. Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., Walker, G. J., Hayward, N., and Dracopoli, N. C. 1996, Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12:, 97–9.CrossRefPubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Lili Yamasaki

There are no affiliations available

Personalised recommendations