Skip to main content
SpringerLink
Log in

Modeling Cell Cycle Control and Cancer with pRB Tumor Suppressor

  • Chapter
  • First Online:
Cell Cycle Regulation

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 42))

Abstract

Cancer is a complex syndrome of diseases characterized by the increased abundance of cells that disrupts the normal tissue architecture within an organism. Defining one universal mechanism underlying cancer with the hope of designing a magic bullet against cancer is impossible, largely because there is so much variation between various types of cancer and different individuals. However, we have learned much in past decades about different journeys that a normal cell takes to become cancerous, and that the delicate balance between oncogenes and tumor suppressor is upset, favoring growth and survival of the tumor cell. One of the most important cellular barriers to cancer development is the retinoblastoma tumor suppressor (pRB) pathway, which is inactivated in a wide range of human tumors and controls cell cycle progression via repression of the E2F/DP transcription factor family. Much of the clarity with which we view tumor suppression via pRB is due to our belief in the universality of the cell cycle and our attempts to model tumor pathways in vivo, nowhere so evident as in the multitude of data emerging from mutant mouse models that have been engineered to understand how cell cycle regulators limit growth in vivo and how deregulation of these regulators facilitates cancer development. In spite of this clarity, we have witnessed with incredulity several stunning results in the last 2 years that have challenged the very foundations of the cell cycle paradigm and made us question seriously how important these cell cycle regulators actually are.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. al-Ubaidi MR, Font RL, Quiambao AB, Keener MJ, Liou GI, Overbeek PA, Baehr W (1992) Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter. J Cell Biol 119:1681–1687

    PubMed  CAS  Google Scholar 

  2. Attwooll C, Denchi EL, Helin K (2004) The E2F family: specific functions and overlapping interests. Embo J 23:4709–4716

    PubMed  CAS  Google Scholar 

  3. Balmain A (2001) Cancer genetics: from Boveri and Mendel to microarrays. Nat Rev Cancer 1:77–82

    PubMed  CAS  Google Scholar 

  4. Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33:238–244

    PubMed  CAS  Google Scholar 

  5. Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P (2003) Cdk2 knockout mice are viable. Curr Biol 13:1775–1785

    PubMed  CAS  Google Scholar 

  6. Brandeis M, Rosewell I, Carrington M, Crompton T, Jacobs MA, Kirk J, Gannon J, Hunt T (1998) Cyclin B2-null mice develop normally and are fertile whereas cyclin B1-null mice die in utero. Proc Natl Acad Sci USA 95:4344–4349

    PubMed  CAS  Google Scholar 

  7. Brown VD, Gallie BL (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

    PubMed  CAS  Google Scholar 

  8. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377:552–557

    PubMed  CAS  Google Scholar 

  9. Brugarolas J, Bronson RT, Jacks T (1998) p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells. J Cell Biol 141:503–514

    PubMed  CAS  Google Scholar 

  10. Chan HM, Krstic-Demonacos M, Smith L, Demonacos C, La Thangue NB (2001) Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Cell Biol 3:667–674

    PubMed  CAS  Google Scholar 

  11. Chen D, Livne-bar I, Vanderluit JL, Slack RS, Agochiya M, Bremner R (2004) Cell-specific effects of RB or RB=p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma. Cancer Cell 5:539–551

    PubMed  CAS  Google Scholar 

  12. Chen PL, Riley DJ, Chen Y, Lee WH (1996) Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C=EBPs. Genes Dev 10:2794–2804

    PubMed  CAS  Google Scholar 

  13. Ciemerych MA, Kenney AM, Sicinska E, Kalaszczynska I, Bronson RT, Rowitch DH, Gardner H, Sicinski P (2002) Development of mice expressing a single D-type cyclin. Genes Dev 16:3277–3289

    CAS  Google Scholar 

  14. Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, Berns A, te Riele H (1992) Requirement for a functional Rb-1 gene in murine development. Nature 359:328–330

    PubMed  CAS  Google Scholar 

  15. Classon M, Harlow E (2002) The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2:910–917

    PubMed  CAS  Google Scholar 

  16. Cloud JE, Rogers C, Reza TL, Ziebold U, Stone JR, Picard MH, Caron AM, Bronson RT, Lees JA (2002) Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo. Mol Cell Biol 22:2663–2672

    PubMed  CAS  Google Scholar 

  17. Cobrinik D, Lee MH, Hannon G, Mulligan G, Bronson RT, Dyson N, Harlow E, Beach D, Weinberg RA, Jacks T (1996) Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev 10:1633–1644

    PubMed  CAS  Google Scholar 

  18. Dannenberg JH, van Rossum A, Schuijff L, te Riele H (2000) Ablation of the retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev 14:3051–3064

    PubMed  CAS  Google Scholar 

  19. Dannenberg JH, Schuijff L, Dekker M, van der Valk M, te Riele H (2004) Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev 18:2952–2962

    PubMed  CAS  Google Scholar 

  20. de Bruin A, Wu L, Saavedra HI, Wilson P, Yang Y, Rosol TJ, Weinstein M, Robinson ML, Leone G (2003) Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice. Proc Natl Acad Sci USA 100:6546–6551

    PubMed  Google Scholar 

  21. DeCaprio JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee WH, Marsilio E, Paucha E, Livingston DM (1988) SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54:275–283

    PubMed  CAS  Google Scholar 

  22. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P (1995) Mice lacking p21CIP1=WAF1undergo normal development, but are defective in G1 checkpoint control. Cell 82:675–684

    PubMed  CAS  Google Scholar 

  23. Dyer MA, Bremner R (2005) The search for the retinoblastoma cell of origin. Nat Rev Cancer 5:91–101

    PubMed  CAS  Google Scholar 

  24. Dyson N, Howley PM, Munger K, Harlow E (1989) The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937

    PubMed  CAS  Google Scholar 

  25. Ephrussi B, Davidson RL, Weiss MC, Harris H, Klein G (1969) Malignancy of somatic cell hybrids. Nature 224:1314–1316

    PubMed  CAS  Google Scholar 

  26. Ewart-Toland A, Briassouli P, de Koning JP, Mao JH, Yuan J, Chan F, MacCarthy-Morrogh L, Ponder BA, Nagase H, Burn J, Ball S, Almeida M, Linardopoulos S, Balmain A (2003) Identification of Stk6=STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Genet 34:403–412

    PubMed  CAS  Google Scholar 

  27. Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C (1995) Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev 9:2364–2372

    PubMed  CAS  Google Scholar 

  28. Ferguson KL, Vanderluit JL, Hebert JM, McIntosh WC, Tibbo E, MacLaurin JG, Park DS, Wallace VA, Vooijs M, McConnell SK, Slack RS (2002) Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development. Embo J 21:3337–3346

    PubMed  CAS  Google Scholar 

  29. Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM (1996) A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice. Cell 85:733–744

    PubMed  CAS  Google Scholar 

  30. Field SJ, Tsai FY, Kuo F, Zubiaga AM, Kaelin WG, Jr, Livingston DM, Orkin SH, Greenberg ME (1996) E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85:549–561

    PubMed  CAS  Google Scholar 

  31. Gaubatz S, Lindeman GJ, Ishida S, Jakoi L, Nevins JR, Livingston DM, Rempel RE (2000) E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol Cell 6:729–735

    PubMed  CAS  Google Scholar 

  32. Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li T, Weinberg RA, Sicinski P (1999) Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 97:767–777

    PubMed  CAS  Google Scholar 

  33. Geng Y, Yu Q, Sicinska E, Das M, Schneider JE, Bhattacharya S, Rideout WM, Bronson RT, Gardner H, Sicinski P (2003) Cyclin E ablation in the mouse. Cell 114:431–443

    PubMed  CAS  Google Scholar 

  34. Gladden AB, Diehl JA (2003) Cell cycle progression without cyclin E=CDK2: breaking down the walls of dogma. Cancer Cell 4:160–162

    PubMed  CAS  Google Scholar 

  35. Gu W, Schneider JW, Condorelli G, Kaushal S, Mahdavi V, Nadal-Ginard B (1993) Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell 72:309–324

    PubMed  CAS  Google Scholar 

  36. Harrison DJ, Hooper ML, Armstrong JF, Clarke AR (1995) Effects of heterozygosity for the Rb–1t19neo allele in the mouse. Oncogene 10:1615–1620

    PubMed  CAS  Google Scholar 

  37. Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, Komoto Y, Okada A, Ohishi S, Nabetani A, Morisaki H, Nakayama M, Niikawa N, Mukai T (1996) An imprinted gene p57KIP2is mutated in Beckwith–Wiedemann syndrome. Nat Genet 14:171–173

    PubMed  CAS  Google Scholar 

  38. Hernando E, Nahle Z, Juan G, Diaz-Rodriguez E, Alaminos M, Hemann M, Michel L, Mittal V, Gerald W, Benezra R, Lowe SW, Cordon-Cardo C (2004) Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430:797–802

    PubMed  CAS  Google Scholar 

  39. Howes KA, Ransom N, Papermaster DS, Lasudry JG, Albert DM, Windle JJ (1994) Apoptosis or retinoblastoma: alternative fates of photoreceptors expressing the HPV-16 E7 gene in the presence or absence of p53. Genes Dev 8:1300–1310

    PubMed  CAS  Google Scholar 

  40. Hu N, Gutsmann A, Herbert DC, Bradley A, Lee WH, Lee EY (1994) Heterozygous Rb-1 delta 20=+ mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9:1021–1027

    PubMed  CAS  Google Scholar 

  41. Huang HJ, Yee JK, Shew JY, Chen PL, Bookstein R, Friedmann T, Lee EY, Lee WH (1988) Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science 242:1563–1566

    PubMed  CAS  Google Scholar 

  42. Humbert PO, Rogers C, Ganiatsas S, Landsberg RL, Trimarchi JM, Dandapani S, Brugnara C, Erdman S, Schrenzel M, Bronson RT, Lees JA (2000) E2F4 is essential for normal erythrocyte maturation and neonatal viability. Mol Cell 6:281–291

    PubMed  CAS  Google Scholar 

  43. Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S, Lees JA (2000) E2f3 is critical for normal cellular proliferation. Genes Dev 14:690–703

    PubMed  CAS  Google Scholar 

  44. Iavarone A, King ER, Dai XM, Leone G, Stanley ER, Lasorella A (2004) Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature 432:1040–1045

    PubMed  CAS  Google Scholar 

  45. Iglesias A, Murga M, Laresgoiti U, Skoudy A, Bernales I, Fullaondo A, Moreno B, Lloreta J, Field SJ, Real FX, Zubiaga AM (2004) Diabetes and exocrine pancreatic insufficiency in E2F1=E2F2 double-mutant mice. J Clin Invest 113:1398–1407

    PubMed  CAS  Google Scholar 

  46. Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH, Kaelin WG Jr (2000) Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature 407:645–648

    PubMed  CAS  Google Scholar 

  47. Ishida S, Huang E, Zuzan H, Spang R, Leone G, West M, Nevins JR (2001) Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol Cell Biol 21:4684–4699

    PubMed  CAS  Google Scholar 

  48. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA (1992) Effects of an Rb mutation in the mouse. Nature 359:295–300

    PubMed  CAS  Google Scholar 

  49. Kalma Y, Marash L, Lamed Y, Ginsberg D (2001) Expression analysis using DNA microarrays demonstrates that E2F-1 up-regulates expression of DNA replication genes including replication protein A2. Oncogene 20:1379–1387

    PubMed  CAS  Google Scholar 

  50. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440

    PubMed  CAS  Google Scholar 

  51. Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91:649–659

    PubMed  CAS  Google Scholar 

  52. Kaye FJ (2002) RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer. Oncogene 21:6908–6914

    PubMed  CAS  Google Scholar 

  53. Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A (1996) Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27Kip1. Cell 85:721–732

    PubMed  CAS  Google Scholar 

  54. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823

    PubMed  Google Scholar 

  55. Knudson AG (2001) Two genetic hits (more or less) to cancer. Nat Rev Cancer 1:157–162

    PubMed  CAS  Google Scholar 

  56. Kohn MJ, Bronson RT, Harlow E, Dyson NJ, Yamasaki L (2003) Dp1 is required for extra-embryonic development. Development 130:1295–1305

    PubMed  CAS  Google Scholar 

  57. Kohn MJ, Leung SW, Criniti V, Agromayor M, Yamasaki L (2004) Dp1 is largely dispensable for embryonic development. Mol Cell Biol 24:7197–7205

    PubMed  CAS  Google Scholar 

  58. Kozar K, Ciemerych MA, Rebel VI, Shigematsu H, Zagozdzon A, Sicinska E, Geng Y, Yu Q, Bhattacharya S, Bronson RT, Akashi K, Sicinski P (2004) Mouse development and cell proliferation in the absence of D-cyclins. Cell 118:477–491

    PubMed  CAS  Google Scholar 

  59. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A (2001) Loss of p16Ink4aconfers susceptibility to metastatic melanoma in mice. Nature 413:83–86

    PubMed  CAS  Google Scholar 

  60. Kristjansdottir K, Rudolph J (2004) Cdc25 phosphatases and cancer. Chem Biol 11:1043–1051

    PubMed  CAS  Google Scholar 

  61. Lasorella A, Noseda M, Beyna M, Yokota Y, Iavarone A (2000) Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407:592–598

    PubMed  CAS  Google Scholar 

  62. LeCouter JE, Kablar B, Hardy WR, Ying C, Megeney LA, May LL, Rudnicki MA (1998) Strain-dependent myeloid hyperplasia, growth deficiency, and accelerated cell cycle in mice lacking the Rb-related p107 gene. Mol Cell Biol 18:7455–7465

    PubMed  CAS  Google Scholar 

  63. LeCouter JE, Kablar B, Whyte PF, Ying C, Rudnicki MA (1998) Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene. Development 125:4669–4679

    PubMed  CAS  Google Scholar 

  64. Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359:288–294

    PubMed  CAS  Google Scholar 

  65. Lee EY, Cam H, Ziebold U, Rayman JB, Lees JA, Dynlacht BD (2002) E2F4 loss suppresses tumorigenesis in Rb mutant mice. Cancer Cell 2:463–472

    PubMed  CAS  Google Scholar 

  66. Lee MH, Williams BO, Mulligan G, Mukai S, Bronson RT, Dyson N, Harlow E, Jacks T (1996) Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev 10:1621–1632

    PubMed  CAS  Google Scholar 

  67. Leung SW, Wloga EH, Castro AF, Nguyen T, Bronson RT, Yamasaki L (2004) A dynamic switch in Rb+=– mediated neuroendocrine Tumorigenesis. Oncogene 23:3296–3307

    PubMed  CAS  Google Scholar 

  68. Li FX, Zhu JW, Hogan CJ, DeGregori J (2003) Defective gene expression, S phase progression, and maturation during hematopoiesis in E2F1=E2F2 mutant mice. Mol Cell Biol 23:3607–3622

    PubMed  CAS  Google Scholar 

  69. Li FX, Zhu JW, Tessem JS, Beilke J, Varella-Garcia M, Jensen J, Hogan CJ, DeGregori J (2003) The development of diabetes in E2f1=E2f2 mutant mice reveals important roles for bone marrow-derived cells in preventing islet cell loss. Proc Natl Acad Sci USA 100:12935–12940

    PubMed  CAS  Google Scholar 

  70. Lindeman GJ, Dagnino L, Gaubatz S, Xu Y, Bronson RT, Warren HB, Livingston DM (1998) A specific, nonproliferative role for E2F-5 in choroid plexus function revealed by gene targeting. Genes Dev 12:1092–1098

    PubMed  CAS  Google Scholar 

  71. Lipinski MM, Macleod KF, Williams BO, Mullaney TL, Crowley D, Jacks T (2001) Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system. Embo J 20:3402–3413

    PubMed  CAS  Google Scholar 

  72. Lissy NA, Davis PK, Irwin M, Kaelin WG, Dowdy SF (2000) A common E2F-1 and p73 pathway mediates cell death induced by TCR activation. Nature 407:642–645

    PubMed  CAS  Google Scholar 

  73. Ma Y, Croxton R, Moorer RL Jr, Cress WD (2002) Identification of novel E2F1-regulated genes by microarray. Arch Biochem Biophys 399:212–224

    PubMed  CAS  Google Scholar 

  74. Maandag EC, van der Valk M, Vlaar M, Feltkamp C, O'Brien J, van Roon M, van der Lugt N, Berns A, te Riele H (1994) Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. Embo J 13:4260–4268

    CAS  Google Scholar 

  75. Macleod KF, Hu Y, Jacks T (1996) Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. Embo J 15:6178–6188

    PubMed  CAS  Google Scholar 

  76. MacPherson D, Sage J, Crowley D, Trumpp A, Bronson RT, Jacks T (2003) Conditional mutation of Rb causes cell cycle defects without apoptosis in the central nervous system. Mol Cell Biol 23:1044–1053

    PubMed  CAS  Google Scholar 

  77. MacPherson D, Sage J, Kim T, Ho D, McLaughlin ME, Jacks T (2004) Cell type-specific effects of Rb deletion in the murine retina. Genes Dev 18:1681–1694

    PubMed  CAS  Google Scholar 

  78. Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S, Dubus P, Barbacid M (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118:493–504

    PubMed  CAS  Google Scholar 

  79. Marino S, Vooijs M, van Der Gulden H, Jonkers J, Berns A (2000) Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev 14:994–1004

    PubMed  CAS  Google Scholar 

  80. Marino S, Hoogervoorst D, Brandner S, Berns A (2003) Rb and p107 are required for normal cerebellar development and granule cell survival but not for Purkinje cell persistence. Development 130:3359–3368

    PubMed  CAS  Google Scholar 

  81. Martinez-Balbas MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T (2000) Regulation of E2F1 activity by acetylation. Embo J 19:662–671

    PubMed  CAS  Google Scholar 

  82. Marzio G, Wagener C, Gutierrez MI, Cartwright P, Helin K, Giacca M (2000) E2F family members are differentially regulated by reversible acetylation. J Biol Chem 275:10887–10892

    PubMed  CAS  Google Scholar 

  83. Minna JD, Gazdar AF, Sprang SR, Herz J (2004) Cancer. A bull's eye for targeted lung cancer therapy. Science 304:1458–1461

    PubMed  CAS  Google Scholar 

  84. Morgan DO (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13:261–291

    PubMed  CAS  Google Scholar 

  85. Morgenbesser SD, Williams BO, Jacks T, DePinho RA (1994) p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 371:72–74

    PubMed  CAS  Google Scholar 

  86. Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Muller H, Helin K (2001) Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 3:552–558

    PubMed  CAS  Google Scholar 

  87. Morris EJ, Dyson NJ (2001) Retinoblastoma protein partners. Adv Cancer Res 82:1–54

    PubMed  CAS  Google Scholar 

  88. Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM, Arnold A (1991) A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350:512–515

    PubMed  CAS  Google Scholar 

  89. Murga M, Fernandez-Capetillo O, Field SJ, Moreno B, Borlado LR, Fujiwara Y, Balomenos D, Vicario A, Carrera AC, Orkin SH, Greenberg ME, Zubiaga AM (2001) Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity. Immunity 15:959–970

    PubMed  CAS  Google Scholar 

  90. Murphy M, Stinnakre MG, Senamaud-Beaufort C, Winston NJ, Sweeney C, Kubelka M, Carrington M, Brechot C, Sobczak-Thepot J (1997) Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nat Genet 15:83–86

    PubMed  CAS  Google Scholar 

  91. Nahle Z, Polakoff J, Davuluri RV, McCurrach ME, Jacobson MD, Narita M, Zhang MQ, Lazebnik Y, Bar-Sagi D, Lowe SW (2002) Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol 4:859–864

    PubMed  CAS  Google Scholar 

  92. Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY (1996) Mice lacking p27Kip1display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85:707–720

    PubMed  CAS  Google Scholar 

  93. Nguyen DX, Baglia LA, Huang SM, Baker CM, McCance DJ (2004) Acetylation regulates the differentiation-specific functions of the retinoblastoma protein. Embo J 23:1609–1618

    PubMed  CAS  Google Scholar 

  94. Nikitin AY, Juarez-Perez MI, Li S, Huang L, Lee WH (1999) RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+=– mice. Proc Natl Acad Sci USA 96:3916–3921

    PubMed  CAS  Google Scholar 

  95. O'Keefe D, Dao D, Zhao L, Sanderson R, Warburton D, Weiss L, Anyane-Yeboa K, Tycko B (1997) Coding mutations in p57KIP2are present in some cases of Beckwith–Wiedemann syndrome but are rare or absent in Wilms tumors. Am J Hum Genet 61:295–303

    PubMed  Google Scholar 

  96. Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, Barbero JL, Malumbres M, Barbacid M (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35:25–31

    PubMed  CAS  Google Scholar 

  97. Pagano M, Benmaamar R (2003) When protein destruction runs amok, malignancy is on the loose. Cancer Cell 4:251–256

    PubMed  CAS  Google Scholar 

  98. Pagano M, Jackson PK (2004) Wagging the dogma; tissue-specific cell cycle control in the mouse embryo. Cell 118:535–538

    PubMed  CAS  Google Scholar 

  99. Palmero I, Peters G (1996) Perturbation of cell cycle regulators in human cancer. Cancer Surv 27:351–367

    CAS  Google Scholar 

  100. Parisi T, Beck AR, Rougier N, McNeil T, Lucian L, Werb Z, Amati B (2003) Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells. Embo J 22:4794–4803

    PubMed  CAS  Google Scholar 

  101. Park MS, Rosai J, Nguyen HT, Capodieci P, Cordon-Cardo C, Koff A (1999) p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice. Proc Natl Acad Sci USA 96:6382–6387

    PubMed  CAS  Google Scholar 

  102. Pediconi N, Ianari A, Costanzo A, Belloni L, Gallo R, Cimino L, Porcellini A, Screpanti I, Balsano C, Alesse E, Gulino A, Levrero M (2003) Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nat Cell Biol 5:552–558

    PubMed  CAS  Google Scholar 

  103. Peeper DS, Dannenberg JH, Douma S, te Riele H, Bernards R (2001) Escape from premature senescence is not sufficient for oncogenic transformation by Ras. Nat Cell Biol 3:198–203

    PubMed  CAS  Google Scholar 

  104. Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36

    PubMed  CAS  Google Scholar 

  105. Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, 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

    PubMed  CAS  Google Scholar 

  106. Reed SI (2003) Ratchets and clocks: the cell cycle, ubiquitylation and protein turnover. Nat Rev Mol Cell Biol 4:855–864

    PubMed  CAS  Google Scholar 

  107. Rempel RE, Saenz-Robles MT, Storms R, Morham S, Ishida S, Engel A, Jakoi L, Melhem MF, Pipas JM, Smith C, Nevins JR (2000) Loss of E2F4 activity leads to abnormal development of multiple cellular lineages. Mol Cell 6:293–306

    PubMed  CAS  Google Scholar 

  108. Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA, Dynlacht BD (2002) E2F integrates cell cycle progression with DNA repair, replication, and G2=M checkpoints. Genes Dev 16:245–256

    PubMed  CAS  Google Scholar 

  109. Robanus-Maandag E, Dekker M, van der Valk M, Carrozza ML, Jeanny JC, Dannenberg JH, Berns A, te Riele H (1998) p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev 12:1599–1609

    PubMed  CAS  Google Scholar 

  110. Roberts JM, Sherr CJ (2003) Bared essentials of CDK2 and cyclin E. Nat Genet 35:9–10

    PubMed  CAS  Google Scholar 

  111. Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams B, Theodorou E, Jacks T (2000) Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalization. Genes Dev 14:3037–3050

    PubMed  CAS  Google Scholar 

  112. Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T (2003) Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424:223–228

    PubMed  CAS  Google Scholar 

  113. Sellers WR, Novitch BG, Miyake S, Heith A, Otterson GA, Kaye FJ, Lassar AB, Kaelin WG 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

    PubMed  CAS  Google Scholar 

  114. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA (1996) Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:27–37

    PubMed  CAS  Google Scholar 

  115. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA (2001) Loss of p16Ink4awith retention of p19Arfpredisposes mice to tumorigenesis. Nature 413:86–91

    PubMed  CAS  Google Scholar 

  116. Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677

    PubMed  CAS  Google Scholar 

  117. Sherr CJ (2001) The INK4a=ARF network in tumour suppression. Nat Rev Mol Cell Biol 2:731–737

    PubMed  CAS  Google Scholar 

  118. Sherr CJ (2001) Parsing Ink4a=Arf: "pure" p16-null mice. Cell 106:531–534

    PubMed  CAS  Google Scholar 

  119. Sherr CJ, Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Genes Dev 18:2699–2711

    PubMed  CAS  Google Scholar 

  120. Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ, Weinberg RA (1995) Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621–630

    PubMed  CAS  Google Scholar 

  121. Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA (1996) Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384:470–474

    PubMed  CAS  Google Scholar 

  122. Sicinska E, Aifantis I, Le Cam L, Swat W, Borowski C, Yu Q, Ferrando AA, Levin SD, Geng Y, von Boehmer H, Sicinski P (2003) Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 4:451–461

    PubMed  CAS  Google Scholar 

  123. Spike BT, Dirlam A, Dibling BC, Marvin J, Williams BO, Jacks T, Macleod KF (2004) The Rb tumor suppressor is required for stress erythropoiesis. Embo J 23:4319–4329

    PubMed  CAS  Google Scholar 

  124. Stevaux O, Dyson NJ (2002) A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 14:684–691

    PubMed  CAS  Google Scholar 

  125. Storre J, Elsasser HP, Fuchs M, Ullmann D, Livingston DM, Gaubatz S (2002) Homeotic transformations of the axial skeleton that accompany a targeted deletion of E2f6. EMBO Rep 3:695–700

    PubMed  CAS  Google Scholar 

  126. Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426

    PubMed  CAS  Google Scholar 

  127. Thomas DM, Carty SA, Piscopo DM, Lee JS, Wang WF, Forrester WC, Hinds PW (2001) The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol Cell 8:303–316

    PubMed  CAS  Google Scholar 

  128. Trimarchi JM, Lees JA (2002) Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 3:11–20

    PubMed  CAS  Google Scholar 

  129. Tsai KY, Hu Y, Macleod KF, Crowley D, Yamasaki L, Jacks T (1998) Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell 2:293–304

    PubMed  CAS  Google Scholar 

  130. Tsai KY, MacPherson D, Rubinson DA, Crowley D, Jacks T (2002) ARF is not required for apoptosis in Rb mutant mouse embryos. Curr Biol 12:159–163

    PubMed  CAS  Google Scholar 

  131. Tsai KY, MacPherson D, Rubinson DA, Nikitin AY, Bronson R, Mercer KL, Crowley D, Jacks T (2002) ARF mutation accelerates pituitary tumor development in Rb+=– mice. Proc Natl Acad Sci USA 99:16865–16870

    PubMed  CAS  Google Scholar 

  132. Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H (1999) Targeted disruption of CDK4 delays cell cycle entry with enhanced p27Kip1activity. Mol Cell Biol 19:7011–7019

    PubMed  CAS  Google Scholar 

  133. Vooijs M, te Riele H, van der Valk M, Berns A (2002) Tumor formation in mice with somatic inactivation of the retinoblastoma gene in interphotoreceptor retinol binding protein-expressing cells. Oncogene 21:4635–4645

    PubMed  CAS  Google Scholar 

  134. Wang J, Chenivesse X, Henglein B, Brechot C (1990) Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343:555–557

    PubMed  CAS  Google Scholar 

  135. Weinmann AS, Yan PS, Oberley MJ, Huang TH, Farnham PJ (2002) Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes Dev 16:235–244

    PubMed  CAS  Google Scholar 

  136. Wells J, Graveel CR, Bartley SM, Madore SJ, Farnham PJ (2002) The identification of E2F1-specific target genes. Proc Natl Acad Sci USA 99:3890–3895

    PubMed  CAS  Google Scholar 

  137. Wikonkal NM, Remenyik E, Knezevic D, Zhang W, Liu M, Zhao H, Berton TR, Johnson DG, Brash DE (2003) Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice. Nat Cell Biol 5:655–660

    PubMed  CAS  Google Scholar 

  138. Williams BO, Remington L, Albert DM, Mukai S, Bronson RT, Jacks T (1994) Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet 7:480–484

    PubMed  CAS  Google Scholar 

  139. Williams BO, Schmitt EM, Remington L, Bronson RT, Albert DM, Weinberg RA, Jacks T (1994) Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. Embo J 13:4251–4259

    PubMed  CAS  Google Scholar 

  140. Windle JJ, Albert DM, O'Brien JM, Marcus DM, Disteche CM, Bernards R, Mellon PL (1990) Retinoblastoma in transgenic mice. Nature 343:665–669

    PubMed  CAS  Google Scholar 

  141. Wloga EH, Criniti V, Yamasaki L, Bronson RT (2004) Lymphomagenesis and female-specific lethality in p53-deficient mice occur independently of E2f1. Nat Cell Biol 6:565–567

    PubMed  CAS  Google Scholar 

  142. Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML, Leone G (2001) The E2F1–3 transcription factors are essential for cellular proliferation. Nature 414:457–462

    PubMed  CAS  Google Scholar 

  143. Wu L, de Bruin A, Saavedra HI, Starovic M, Trimboli A, Yang Y, Opavska J, Wilson P, Thompson JC, Ostrowski MC, Rosol TJ, Woollett LA, Weinstein M, Cross JC, Robinson ML, Leone G (2003) Extra-embryonic function of Rb is essential for embryonic development and viability. Nature 421:942–947

    PubMed  CAS  Google Scholar 

  144. Yamasaki L, Jacks T, Bronson R, Goillot E, Harlow E, Dyson NJ (1996) Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85:537–548

    PubMed  CAS  Google Scholar 

  145. Yamasaki L, Bronson R, Williams BO, Dyson NJ, Harlow E, Jacks T (1998) Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1+=– mice. Nat Genet 18:360–364

    PubMed  CAS  Google Scholar 

  146. Yan Y, Frisen J, Lee MH, Massague J, Barbacid M (1997) Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev 11:973–983

    PubMed  CAS  Google Scholar 

  147. Zachariae W, Nasmyth K (1999) Whose end is destruction: cell division and the anaphase-promoting complex. Genes Dev 13:2039–2058

    PubMed  CAS  Google Scholar 

  148. Zacksenhaus E, Jiang Z, Chung D, Marth JD, Phillips RA, Gallie BL (1996) pRb controls proliferation, differentiation, and death of skeletal muscle cells and other lineages during embryogenesis. Genes Dev 10:3051–3064

    PubMed  CAS  Google Scholar 

  149. Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA, Elledge SJ (1997) Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith–Wiedemann syndrome. Nature 387:151–158

    PubMed  CAS  Google Scholar 

  150. Zhang J, Gray J, Wu L, Leone G, Rowan S, Cepko CL, Zhu X, Craft CM, Dyer MA (2004) Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nat Genet 36:351–360

    PubMed  Google Scholar 

  151. Zhang J, Schweers B, Dyer MA (2004) The first knockout mouse model of retinoblastoma. Cell Cycle 3:952–959

    PubMed  CAS  Google Scholar 

  152. Zhu JW, Field SJ, Gore L, Thompson M, Yang H, Fujiwara Y, Cardiff RD, Greenberg M, Orkin SH, DeGregori J (2001) E2F1 and E2F2 determine thresholds for antigen-induced T-cell proliferation and suppress tumorigenesis. Mol Cell Biol 21:8547–8564

    PubMed  CAS  Google Scholar 

  153. Ziebold U, Reza T, Caron A, Lees JA (2001) E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev 15:386–391

    PubMed  CAS  Google Scholar 

  154. Ziebold U, Lee EY, Bronson RT, Lees JA (2003) E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. Mol Cell Biol 23:6542–6552

    PubMed  CAS  Google Scholar 

  155. Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC (1996) Germline mutations in the p16INK4abinding domain of CDK4 in familial melanoma. Nat Genet 12:97–99

    PubMed  CAS  Google Scholar 

  156. zur Hausen H (2002) Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, 10027, New York, NY, USA

    Lili Yamasaki

Authors
  1. Lili Yamasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Philipp Kaldis

Rights and permissions

Reprints and permissions

About this chapter

Cite this chapter

Yamasaki, L. Modeling Cell Cycle Control and Cancer with pRB Tumor Suppressor. In: Kaldis, P. (eds) Cell Cycle Regulation. Results and Problems in Cell Differentiation, vol 42. Springer, Berlin, Heidelberg. https://doi.org/10.1007/b136682

Download citation

Publish with us

Policies and ethics

Search

Navigation