Protein & Cell

, Volume 2, Issue 11, pp 864–878 | Cite as

Conserved RB functions in development and tumor suppression

  • Gabriel M. Gordon
  • Wei DuEmail author


The variety of human cancers in which the retinoblastoma protein pRb is inactivated reflects both its broad importance for tumor suppression and its multitude of cellular functions. Accumulating evidence indicates that pRb contributes to a diversity of cellular functions, including cell proliferation, differentiation, cell death, and genome stability. pRb performs these diverse functions through the formation of large complexes that include E2F transcription factors and chromatin regulators. In this review we will discuss some of the recent advances made in understanding the structure and function of pRb as they relate to tumor suppression, and highlight research using Drosophila melanogaster that reveals important, evolutionarily conserved functions of the RB family.


RB E2F Drosophila Rbf cell cycle chromatin modification 


  1. Attwooll, C., Lazzerini Denchi, E., and Helin, K. (2004). The E2F family: specific functions and overlapping interests. Embo J 23, 4709–4716.Google Scholar
  2. Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.V., Kolettas, E., Niforou, K., Zoumpourlis, V.C., et al. (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637.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, 124–125.Google Scholar
  4. Benevolenskaya, E.V., Murray, H.L., Branton, P., Young, R.A., and Kaelin, W.G. Jr. (2005). Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol Cell 18, 623–635.Google Scholar
  5. Bergmann, A., Agapite, J., McCall, K., and Steller, H. (1998). The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling. Cell 95, 331–341.Google Scholar
  6. Bester, A.C., Roniger, M., Oren, Y.S., Im, M.M., Sarni, D., Chaoat, M., Bensimon, A., Zamir, G., Shewach, D.S., and Kerem, B. (2011). Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145, 435–446.Google Scholar
  7. Bier, E. (2005). Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6, 9–23.Google Scholar
  8. Binné, U.K., Classon, M.K., Dick, F.A., Wei, W., Rape, M., Kaelin, W. G. Jr, Näär, A.M., and Dyson, N.J. (2007). Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol 9, 225–232.Google Scholar
  9. Bosco, E.E., Wang, Y., Xu, H., Zilfou, J.T., Knudsen, K.E., Aronow, B. J., Lowe, S.W., and Knudsen, E.S. (2007). The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. J Clin Invest 117, 218–228.Google Scholar
  10. Bourgo, R.J., Thangavel, C., Ertel, A., Bergseid, J., McClendon, A.K., Wilkens, L., Witkiewicz, A.K., Wang, J.Y., and Knudsen, E.S. (2011). RB restricts DNA damage-initiated tumorigenesis through an LXCXE-dependent mechanism of transcriptional control. Mol Cell 43, 663–672.Google Scholar
  11. Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., Sedivy, J.M., Kinzler, K.W., and Vogelstein, B. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501.Google Scholar
  12. Burke, J.R., Deshong, A.J., Pelton, J.G., and Rubin, S.M. (2010). Phosphorylation-induced conformational changes in the retinoblastoma protein inhibit E2F transactivation domain binding. J Biol Chem 285, 16286–16293.Google Scholar
  13. Burkhart, D.L., and Sage, J. (2008). Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8, 671–682.Google Scholar
  14. Buttitta, L.A., Katzaroff, A.J., Perez, C.L., de la Cruz, A., and Edgar, B. A. (2007). A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila. Dev Cell 12, 631–643.Google Scholar
  15. Calo, E., Quintero-Estades, J.A., Danielian, P.S., Nedelcu, S., Berman, S.D., and Lees, J.A. (2010). Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114.Google Scholar
  16. Chauveinc, L., Mosseri, V., Quintana, E., Desjardins, L., Schlienger, P., Doz, F., and Dutrillaux, B. (2001). Osteosarcoma following retinoblastoma: age at onset and latency period. Ophthalmic Genet 22, 77–88.Google Scholar
  17. Chen, D., Pacal, M., Wenzel, P., Knoepfler, P.S., Leone, G., and Bremner, R. (2009a). Division and apoptosis of E2f-deficient retinal progenitors. Nature 462, 925–929.Google Scholar
  18. Chen, H.Z., Tsai, S.Y., and Leone, G. (2009b). Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer 9, 785–797.Google Scholar
  19. Chicas, A., Wang, X., Zhang, C., McCurrach, M., Zhao, Z., Mert, O., Dickins, R.A., Narita, M., Zhang, M., and Lowe, S.W. (2010). Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 17, 376–387.Google Scholar
  20. Chin, L., Hahn, W.C., Getz, G., and Meyerson, M. (2011). Making sense of cancer genomic data. Genes Dev 25, 534–555.Google Scholar
  21. Chong, J.L., Wenzel, P.L., Sáenz-Robles, M.T., Nair, V., Ferrey, A., Hagan, J.P., Gomez, Y.M., Sharma, N., Chen, H.Z., Ouseph, M., et al. (2009). E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462, 930–934.Google Scholar
  22. Christensen, J., Agger, K., Cloos, P.A., Pasini, D., Rose, S., Sennels, L., Rappsilber, J., Hansen, K.H., Salcini, A.E., and Helin, K. (2007). RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 128, 1063–1076.Google Scholar
  23. Claudio, P.P., Zamparelli, A., Garcia, F.U., Claudio, L., Ammirati, G., Farina, A., Bovicelli, A., Russo, G., Giordano, G.G., McGinnis, D. E., et al. (2002). Expression of cell-cycle-regulated proteins pRb2/ p130, p107, p27(kip1), p53, mdm-2, and Ki-67 (MIB-1) in prostatic gland adenocarcinoma. Clin Cancer Res 8, 1808–1815.Google Scholar
  24. Coschi, C.H., Martens, A.L., Ritchie, K., Francis, S.M., Chakrabarti, S., Berube, N.G., and Dick, F.A. (2010). Mitotic chromosome condensation mediated by the retinoblastoma protein is tumorsuppressive. Genes Dev 24, 1351–1363.Google Scholar
  25. Dannenberg, J.H., Schuijff, L., Dekker, M., van der Valk, M., and te Riele, H. (2004). Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev 18, 2952–2962.Google Scholar
  26. de Nooij, J.C., Letendre, M.A., and Hariharan, I.K. (1996). A cyclindependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell 87, 1237–1247.Google Scholar
  27. Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre’, M., Nuciforo, P.G., Bensimon, A., et al. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642.Google Scholar
  28. Dick, F.A., and Mymryk, J.S. (2011). Sweet DREAMs for Hippo. Genes Dev 25, 889–894.Google Scholar
  29. Dimova, D.K., Stevaux, O., Frolov, M.V., and Dyson, N.J. (2003). Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev 17, 2308–2320.Google Scholar
  30. Du, W., and Dyson, N. (1999). The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis. EMBO J 18, 916–925.Google Scholar
  31. Du, W., and Pogoriler, J. (2006). Retinoblastoma family genes. Oncogene 25, 5190–5200.Google Scholar
  32. Dynlacht, B.D., Flores, O., Lees, J.A., and Harlow, E. (1994). Differential regulation of E2F transactivation by cyclin/cdk2 complexes. Genes Dev 8, 1772–1786.Google Scholar
  33. 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, 817–825.Google Scholar
  34. 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, 487–497.Google Scholar
  35. Feinberg, A.P., and Tycko, B. (2004). The history of cancer epigenetics. Nat Rev Cancer 4, 143–153.Google Scholar
  36. Ferbeyre, G., de Stanchina, E., Querido, E., Baptiste, N., Prives, C., and Lowe, S.W. (2000). PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14, 2015–2027.Google Scholar
  37. Ferres-Marco, D., Gutierrez-Garcia, I., Vallejo, D.M., Bolivar, J., Gutierrez-Aviño, F.J., and Dominguez, M. (2006). Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430–436.Google Scholar
  38. Firth, L.C., and Baker, N.E. (2005). Extracellular signals responsible for spatially regulated proliferation in the differentiating Drosophila eye. Dev Cell 8, 541–551.Google Scholar
  39. Foijer, F., Wolthuis, R.M., Doodeman, V., Medema, R.H., and te Riele, H. (2005). Mitogen requirement for cell cycle progression in the absence of pocket protein activity. Cancer Cell 8, 455–466.Google Scholar
  40. 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, 643–646.Google Scholar
  41. Giangrande, P.H., Zhu, W., Schlisio, S., Sun, X., Mori, S., Gaubatz, S., and Nevins, J.R. (2004). A role for E2F6 in distinguishing G1/Sand G2/M-specific transcription. Genes Dev 18, 2941–2951.Google Scholar
  42. Ginsberg, D. (2002). E2F1 pathways to apoptosis. FEBS Lett 529, 122–125.Google Scholar
  43. Gonzalo, S., García-Cao, M., Fraga, M.F., Schotta, G., Peters, A.H., Cotter, S.E., Eguía, R., Dean, D.C., Esteller, M., Jenuwein, T., et al. (2005). Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 7, 420–428.Google Scholar
  44. Goodrich, D.W. (2003). How the other half lives, the amino-terminal domain of the retinoblastoma tumor suppressor protein. J Cell Physiol 197, 169–180.Google Scholar
  45. Gordon, G.M., and Du, W. (2011). Targeting Rb inactivation in cancers by synthetic lethality. Am J Cancer Res 1, 773–786.Google Scholar
  46. Hallstrom, T.C., Mori, S., and Nevins, J.R. (2008). An E2F1-dependent gene expression program that determines the balance between proliferation and cell death. Cancer Cell 13, 11–22.Google Scholar
  47. Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K., and Elledge, S.J. (1993). The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805–816.Google Scholar
  48. Harrington, L.S., Findlay, G.M., Gray, A., Tolkacheva, T., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N.R., Cheng, S., Shepherd, P.R., et al. (2004). The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166, 213–223.Google Scholar
  49. Hassler, M., Singh, S., Yue, W.W., Luczynski, M., Lakbir, R., Sanchez-Sanchez, F., Bader, T., Pearl, L.H., and Mittnacht, S. (2007). Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture. Mol Cell 28, 371–385.Google Scholar
  50. Hernando, E., Nahlé, Z., Juan, G., Diaz-Rodriguez, E., Alaminos, M., Hemann, M., Michel, L., Mittal, V., Gerald, W., Benezra, R., et al. (2004). Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430, 797–802.Google Scholar
  51. Hiebert, S.W. (1993). Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression. Mol Cell Biol 13, 3384–3391.Google Scholar
  52. 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.Google Scholar
  53. Hirschi, A., Cecchini, M., Steinhardt, R.C., Schamber, M.R., Dick, F. A., and Rubin, S.M. (2010). An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein. Nat Struct Mol Biol 17, 1051–1057.Google Scholar
  54. Hsieh, T.C., Nicolay, B.N., Frolov, M.V., and Moon, N.S. (2010). Tuberous sclerosis complex 1 regulates dE2F1 expression during development and cooperates with RBF1 to control proliferation and survival. PLoS Genet 6, e1001071.Google Scholar
  55. 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, 1021–1027.Google Scholar
  56. Ianari, A., Natale, T., Calo, E., Ferretti, E., Alesse, E., Screpanti, I., Haigis, K., Gulino, A., and Lees, J.A. (2009). Proapoptotic function of the retinoblastoma tumor suppressor protein. Cancer Cell 15, 184–194.Google Scholar
  57. Isaac, C.E., Francis, S.M., Martens, A.L., Julian, L.M., Seifried, L.A., Erdmann, N., Binné, U.K., Harrington, L., Sicinski, P., Bérubé, N. G., et al. (2006). The retinoblastoma protein regulates pericentric heterochromatin. Mol Cell Biol 26, 3659–3671.Google Scholar
  58. 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, 4684–4699.Google Scholar
  59. Iwase, S., Lan, F., Bayliss, P., de la Torre-Ubieta, L., Huarte, M., Qi, H. H., Whetstine, J.R., Bonni, A., Roberts, T.M., and Shi, Y. (2007). The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128, 1077–1088.Google Scholar
  60. Julien, L.A., Carriere, A., Moreau, J., and Roux, P.P. (2010). mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 30, 908–921.Google Scholar
  61. Kaelin, W.G. Jr. (2005). The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5, 689–698.Google Scholar
  62. Kamijo, T., Weber, J.D., Zambetti, G., Zindy, F., Roussel, M.F., and Sherr, C.J. (1998). Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 95, 8292–8297.Google Scholar
  63. Kanber, D., Berulava, T., Ammerpohl, O., Mitter, D., Richter, J., Siebert, R., Horsthemke, B., Lohmann, D., and Buiting, K. (2009). The human retinoblastoma gene is imprinted. PLoS Genet 5, e1000790.Google Scholar
  64. 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, 331–342.Google Scholar
  65. Kaye, F.J., and Harbour, J.W. (2004). For whom the bell tolls: susceptibility to common adult cancers in retinoblastoma survivors. J Natl Cancer Inst 96, 342–343.Google Scholar
  66. Klose, R.J., Yan, Q., Tothova, Z., Yamane, K., Erdjument-Bromage, H., Tempst, P., Gilliland, D.G., Zhang, Y., and Kaelin, W.G. Jr. (2007). The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889–900.Google Scholar
  67. Knudsen, E.S., and Wang, J.Y. (2010). Targeting the RB-pathway in cancer therapy. Clin Cancer Res 16, 1094–1099.Google Scholar
  68. Knudson, A.G. Jr. (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68, 820–823.Google Scholar
  69. Korenjak, M., Taylor-Harding, B., Binné, U.K., Satterlee, J.S., Stevaux, O., Aasland, R., White-Cooper, H., Dyson, N., and Brehm, A. (2004). Native E2F/RBF complexes contain Mybinteracting proteins and repress transcription of developmentally controlled E2F target genes. Cell 119, 181–193.Google Scholar
  70. Lalande, M., Dryja, T.P., Schreck, R.R., Shipley, J., Flint, A., and Latt, S.A. (1984). Isolation of human chromosome 13-specific DNA sequences cloned from flow sorted chromosomes and potentially linked to the retinoblastoma locus. Cancer Genet Cytogenet 13, 283–295.Google Scholar
  71. Lane, M.E., Sauer, K., Wallace, K., Jan, Y.N., Lehner, C.F., and Vaessin, H. (1996). Dacapo, a cyclin-dependent kinase inhibitor, stops cell proliferation during Drosophila development. Cell 87, 1225–1235.Google Scholar
  72. Laurie, N.A., Donovan, S.L., Shih, C.S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., et al. (2006). Inactivation of the p53 pathway in retinoblastoma. Nature 444, 61–66.Google Scholar
  73. 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, 1394–1399.Google Scholar
  74. Lewis, P.W., Beall, E.L., Fleischer, T.C., Georlette, D., Link, A.J., and Botchan, M.R. (2004). Identification of a Drosophila Myb-E2F2/ RBF transcriptional repressor complex. Genes Dev 18, 2929–2940.Google Scholar
  75. Li, B., Gordon, G.M., Du, C.H., Xu, J., and Du, W. (2010). Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17, 469–480.Google Scholar
  76. Li, J., Ran, C., Li, E., Gordon, F., Comstock, G., Siddiqui, H., Cleghorn, W., Chen, H.Z., Kornacker, K., Liu, C.G., et al. (2008). Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development. Dev Cell 14, 62–75.Google Scholar
  77. Lin, W., Cao, J., Liu, J., Beshiri, M.L., Fujiwara, Y., Francis, J., Cherniack, A.D., Geisen, C., Blair, L.P., Zou, M.R., et al. (2011). Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc Natl Acad Sci U S A 108, 13379–13386.Google Scholar
  78. Litovchick, L., Florens, L.A., Swanson, S.K., Washburn, M.P., and DeCaprio, J.A. (2011). DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev 25, 801–813.Google Scholar
  79. Litovchick, L., Sadasivam, S., Florens, L., Zhu, X., Swanson, S.K., Velmurugan, S., Chen, R., Washburn, M.P., Liu, X.S., and DeCaprio, J.A. (2007). Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell 26, 539–551.Google Scholar
  80. Longworth, M.S., Herr, A., Ji, J.Y., and Dyson, N.J. (2008). RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes Dev 22, 1011–1024.Google Scholar
  81. Lopez-Bigas, N., Kisiel, T.A., Dewaal, D.C., Holmes, K.B., Volkert, T. L., Gupta, S., Love, J., Murray, H.L., Young, R.A., and Benevolenskaya, E.V. (2008). Genome-wide analysis of the H3K4 histone demethylase RBP2 reveals a transcriptional program controlling differentiation. Mol Cell 31, 520–530.Google Scholar
  82. Ludlow, J.W., Glendening, C.L., Livingston, D.M., and DeCarprio, J.A. (1993). Specific enzymatic dephosphorylation of the retinoblastoma protein. Mol Cell Biol 13, 367–372.Google Scholar
  83. Lukas, J., Parry, D., Aagaard, L., Mann, D.J., Bartkova, J., Strauss, M., Peters, G., and Bartek, J. (1995). Retinoblastoma-proteindependent cell-cycle inhibition by the tumour suppressor p16. Nature 375, 503–506.Google Scholar
  84. 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, 601–605.Google Scholar
  85. Manning, A.L., Longworth, M.S., and Dyson, N.J. (2010). Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev 24, 1364–1376.Google Scholar
  86. Milet, C., Rincheval-Arnold, A., Mignotte, B., and Guénal, I. (2010). The Drosophila retinoblastoma protein induces apoptosis in proliferating but not in post-mitotic cells. Cell Cycle 9, 97–103.Google Scholar
  87. Miller, C.W., Simon, K., Aslo, A., Kok, K., Yokota, J., Buys, C.H., Terada, M., and Koeffler, H.P. (1992). p53 mutations in human lung tumors. Cancer Res 52, 1695–1698.Google Scholar
  88. Moon, N.S., Di Stefano, L., and Dyson, N. (2006). A gradient of epidermal growth factor receptor signaling determines the sensitivity of rbf1 mutant cells to E2F-dependent apoptosis. Mol Cell Biol 26, 7601–7615.Google Scholar
  89. Moon, N.S., Frolov, M.V., Kwon, E.J., Di Stefano, L., Dimova, D.K., Morris, E.J., Taylor-Harding, B., White, K., and Dyson, N.J. (2005). Drosophila E2F1 has context-specific pro- and antiapoptotic properties during development. Dev Cell 9, 463–475.Google Scholar
  90. Moroni, M.C., Hickman, E.S., Lazzerini Denchi, E., Caprara, G., Colli, E., Cecconi, F., Müller, H., and Helin, K. (2001). Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 3, 552–558.Google Scholar
  91. Müller, 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, 267–285.Google Scholar
  92. Mulligan, G., and Jacks, T. (1998). The retinoblastoma gene family: cousins with overlapping interests. Trends Genet 14, 223–229.Google Scholar
  93. Narita, M., Nũnez, S., Heard, E., Narita, M., Lin, A.W., Hearn, S.A., Spector, D.L., Hannon, G.J., and Lowe, S.W. (2003). Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716.Google Scholar
  94. Nicolay, B.N., Bayarmagnai, B., Islam, A.B., Lopez-Bigas, N., and Frolov, M.V. (2011). Cooperation between dE2F1 and Yki/Sd defines a distinct transcriptional program necessary to bypass cell cycle exit. Genes Dev 25, 323–335.Google Scholar
  95. Nicolay, B.N., Bayarmagnai, B., Moon, N.S., Benevolenskaya, E.V., and Frolov, M.V. (2010). Combined inactivation of pRB and hippo pathways induces dedifferentiation in the Drosophila retina. PLoS Genet 6, e1000918.Google Scholar
  96. Nogueira, V., Park, Y., Chen, C.C., Xu, P.Z., Chen, M.L., Tonic, I., Unterman, T., and Hay, N. (2008). Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14, 458–470.Google Scholar
  97. Ozcan, U., Ozcan, L., Yilmaz, E., Düvel, K., Sahin, M., Manning, B.D., and Hotamisligil, G.S. (2008). Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29, 541–551.Google Scholar
  98. Pan, D. (2010). The hippo signaling pathway in development and cancer. Dev Cell 19, 491–505.Google Scholar
  99. Pearson, M., Carbone, R., Sebastiani, C., Cioce, M., Fagioli, M., Saito, S., Higashimoto, Y., Appella, E., Minucci, S., Pandolfi, P.P., et al. (2000). PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210.Google Scholar
  100. Pickering, M.T., and Kowalik, T.F. (2006). Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation. Oncogene 25, 746–755.Google Scholar
  101. Polyak, K., Lee, M.H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P., and Massagué, J. (1994). Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59–66.Google Scholar
  102. Qin, X.Q., Chittenden, T., Livingston, D.M., and Kaelin, W.G. Jr. (1992). Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev 6, 953–964.Google Scholar
  103. Racek, T., Buhlmann, S., Rüst, F., Knoll, S., Alla, V., and Pützer, B.M. (2008). Transcriptional repression of the prosurvival endoplasmic reticulum chaperone GRP78/BIP by E2F1. J Biol Chem 283, 34305–34314.Google Scholar
  104. Ren, B., Cam, H., Takahashi, Y., Volkert, T., Terragni, J., Young, R.A., and Dynlacht, B.D. (2002). E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev 16, 245–256.Google Scholar
  105. Robertson, K.D., Ait-Si-Ali, S., Yokochi, T., Wade, P.A., Jones, P.L., and Wolffe, A.P. (2000). DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25, 338–342.Google Scholar
  106. Rogoff, H.A., Pickering, M.T., Debatis, M.E., Jones, S., and Kowalik, T.F. (2002). E2F1 induces phosphorylation of p53 that is coincident with p53 accumulation and apoptosis. Mol Cell Biol 22, 5308–5318.Google Scholar
  107. Rubin, S.M., Gall, A.L., Zheng, N., and Pavletich, N.P. (2005). Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release. Cell 123, 1093–1106.Google Scholar
  108. Ruthenburg, A.J., Li, H., Patel, D.J., and Allis, C.D. (2007). Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8, 983–994.Google Scholar
  109. Sage, J., Miller, A.L., Pérez-Mancera, P.A., Wysocki, J.M., and Jacks, T. (2003). Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228.Google Scholar
  110. Sarbassov, D.D., Guertin, D.A., Ali, S.M., and Sabatini, D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101.Google Scholar
  111. Schvartzman, J.M., Duijf, P.H., Sotillo, R., Coker, C., and Benezra, R. (2011). Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. Cancer Cell 19, 701–714.Google Scholar
  112. Searle, J.S., Li, B., and Du, W. (2010). Targeting Rb mutant cancers by inactivating TSC2. Oncotarget 1, 228–232.Google Scholar
  113. Serrano, M., Hannon, G.J., and Beach, D. (1993). A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707.Google Scholar
  114. Shah, O.J., Wang, Z., and Hunter, T. (2004). Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14, 1650–1656.Google Scholar
  115. Sharma, A., Yeow, W.S., Ertel, A., Coleman, I., Clegg, N., Thangavel, C., Morrissey, C., Zhang, X., Comstock, C.E., Witkiewicz, A.K., et al. (2010). The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest 120, 4478–4492.Google Scholar
  116. Sherr, C.J., and McCormick, F. (2002). The RB and p53 pathways in cancer. Cancer Cell 2, 103–112.Google Scholar
  117. Stanelle, J., Stiewe, T., Theseling, C.C., Peter, M., and Pützer, B.M. (2002). Gene expression changes in response to E2F1 activation. Nucleic Acids Res 30, 1859–1867.Google Scholar
  118. Steele, L., Sukhanova, M.J., Xu, J., Gordon, G.M., Huang, Y., Yu, L., and Du, W. (2009). Retinoblastoma family protein promotes normal R8-photoreceptor differentiation in the absence of rhinoceros by inhibiting dE2F1 activity. Dev Biol 335, 228–236.Google Scholar
  119. Stevaux, O., Dimova, D., Frolov, M.V., Taylor-Harding, B., Morris, E., and Dyson, N. (2002). Distinct mechanisms of E2F regulation by Drosophila RBF1 and RBF2. EMBO J 21, 4927–4937.Google Scholar
  120. Stirzaker, C., Millar, D.S., Paul, C.L., Warnecke, P.M., Harrison, J., Vincent, P.C., Frommer, M., and Clark, S.J. (1997). Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res 57, 2229–2237.Google Scholar
  121. Stott, F.J., Bates, S., James, M.C., McConnell, B.B., Starborg, M., Brookes, S., Palmero, I., Ryan, K., Hara, E., Vousden, K.H., et al. (1998). The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17, 5001–5014.Google Scholar
  122. Sukhanova, M.J., Steele, L.J., Zhang, T., Gordon, G.M., and Du, W.. RBF and Rno promote photoreceptor differentiation onset through modulating EGFR signaling in the Drosophila developing eye. Dev Biol. Sep 2, 2011. [Epub ahead of print].Google Scholar
  123. Takahashi, Y., Rayman, J.B., and Dynlacht, B.D. (2000). Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev 14, 804–816.Google Scholar
  124. Talluri, S., Isaac, C.E., Ahmad, M., Henley, S.A., Francis, S.M., Martens, A.L., Bremner, R., and Dick, F.A. (2010). A G1 checkpoint mediated by the retinoblastoma protein that is dispensable in terminal differentiation but essential for senescence. Mol Cell Biol 30, 948–960.Google Scholar
  125. Tanaka, H., Matsumura, I., Ezoe, S., Satoh, Y., Sakamaki, T., Albanese, C., Machii, T., Pestell, R.G., and Kanakura, Y. (2002). E2F1 and c-Myc potentiate apoptosis through inhibition of NFkappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell 9, 1017–1029.Google Scholar
  126. Tanaka-Matakatsu, M., Xu, J., Cheng, L., and Du, W. (2009). Regulation of apoptosis of rbf mutant cells during Drosophila development. Dev Biol 326, 347–356.Google Scholar
  127. Taubert, S., Gorrini, C., Frank, S.R., Parisi, T., Fuchs, M., Chan, H.M., Livingston, D.M., and Amati, B. (2004). E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Mol Cell Biol 24, 4546–4556.Google Scholar
  128. Taylor, B.S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B.S., Arora, V.K., Kaushik, P., Cerami, E., Reva, B., et al. (2010). Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22.Google Scholar
  129. Thomas, D.M., Carty, S.A., Piscopo, D.M., Lee, J.S., Wang, W.F., Forrester, W.C., and Hinds, P.W. (2001). The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol Cell 8, 303–316.Google Scholar
  130. Toyoshima, H., and Hunter, T. (1994). p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67–74.Google Scholar
  131. Treins, C., Warne, P.H., Magnuson, M.A., Pende, M., and Downward, J. (2010). Rictor is a novel target of p70 S6 kinase-1. Oncogene 29, 1003–1016.Google Scholar
  132. Tsai, K.Y., Hu, Y., Macleod, K.F., Crowley, D., Yamasaki, L., and 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.Google Scholar
  133. Tschöp, K., Conery, A.R., Litovchick, L., Decaprio, J.A., Settleman, J., Harlow, E., and Dyson, N. (2011). A kinase shRNA screen links LATS2 and the pRB tumor suppressor. Genes Dev 25, 814–830.Google Scholar
  134. van den Heuvel, S., and Dyson, N.J. (2008). Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 9, 713–724.Google Scholar
  135. van Harn, T., Foijer, F., van Vugt, M., Banerjee, R., Yang, F., Oostra, A., Joenje, H., and te Riele, H. (2010). Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev 24, 1377–1388.Google Scholar
  136. Vernier, M., Bourdeau, V., Gaumont-Leclerc, M.F., Moiseeva, O., Bégin, V., Saad, F., Mes-Masson, A.M., and Ferbeyre, G. (2011). Regulation of E2Fs and senescence by PML nuclear bodies. Genes Dev 25, 41–50.Google Scholar
  137. Voas, M.G., and Rebay, I. (2003). The novel plant homeodomain protein rhinoceros antagonizes Ras signaling in the Drosophila eye. Genetics 165, 1993–2006.Google Scholar
  138. Wang, H., Bauzon, F., Ji, P., Xu, X., Sun, D., Locker, J., Sellers, R.S., Nakayama, K., Nakayama, K.I., Cobrinik, D., et al. (2010). Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1 +/- mice. Nat Genet 42, 83–88.Google Scholar
  139. Wei, W., Ayad, N.G., Wan, Y., Zhang, G.J., Kirschner, M.W., and Kaelin, W.G. Jr. (2004). Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428, 194–198.Google Scholar
  140. Wikenheiser-Brokamp, K.A. (2004). Rb family proteins differentially regulate distinct cell lineages during epithelial development. Development 131, 4299–4310.Google Scholar
  141. Wikenheiser-Brokamp, K.A. (2006a). Retinoblastoma family proteins: insights gained through genetic manipulation of mice. Cell Mol Life Sci 63, 767–780.Google Scholar
  142. Wikenheiser-Brokamp, K.A. (2006b). Retinoblastoma regulatory pathway in lung cancer. Curr Mol Med 6, 783–793.Google Scholar
  143. Williams, B.O., Remington, L., Albert, D.M., Mukai, S., Bronson, R.T., and Jacks, T. (1994). Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet 7, 480–484.Google Scholar
  144. Wirt, S.E., Adler, A.S., Gebala, V., Weimann, J.M., Schaffer, B.E., Saddic, L.A., Viatour, P., Vogel, H., Chang, H.Y., Meissner, A., et al. (2010). G1 arrest and differentiation can occur independently of Rb family function. J Cell Biol 191, 809–825.Google Scholar
  145. Xie, W., Jiang, P., Miao, L., Zhao, Y., Zhimin, Z., Qing, L., Zhu, W.G., and Wu, M. (2006). Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1. Nucleic Acids Res 34, 2046–2055.Google Scholar
  146. 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 Rb1(+/-) mice. Nat Genet 18, 360–364.Google Scholar
  147. 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, 537–548.Google Scholar
  148. Young, A.P., and Longmore, G.D. (2004). Ras protects Rb family null fibroblasts from cell death: a role for AP-1. J Biol Chem 279, 10931–10938.Google Scholar
  149. 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 repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 101, 79–89.Google Scholar
  150. Zhang, Y., Xiong, Y., and Yarbrough, W.G. (1998). ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92, 725–734.Google Scholar
  151. Zhu, L., Harlow, E., and Dynlacht, B.D. (1995). p107 uses a p21CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F. Genes Dev 9, 1740–1752.Google Scholar

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© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Ben May Department for Cancer ResearchUniversity of ChicagoChicagoUSA

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