The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle

Cell Division

Volumn 7, Issue , 2012, Pages

  Henley, Shauna A ^a,b   Dick, Frederick A ^a  

^a UNIVERSITY OF WESTERN ONTARIO   (Canada)

^b Grande Prairie College   (Canada)

Author keywords

Cell cycle; Cyclin dependent kinase; Senescence; Transcription

Indexed keywords

HEXAPODA; MAMMALIA;

EID: 84858055716     PISSN: None     EISSN: 17471028     Source Type: Journal    
DOI: 10.1186/1747-1028-7-10     Document Type: Review

References (165)

1. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986, 323:643-646. 10.1038/323643a0, 2877398.
2. Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EY. Human retinoblastoma susceptibility gene: Cloning, identification, and sequence. Science 1987, 235:1394-1399. 10.1126/science.3823889, 3823889.
3. Dyson N, Howley PM, Munger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989, 243:934-937. 10.1126/science.2537532, 2537532.
4. DeCaprio JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee WH, Marsilio E, Paucha E, Livingston DM. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 1988, 54:275-283. 10.1016/0092-8674(88)90559-4, 2839300.
5. Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA, Harlow E. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 1988, 334:124-129. 10.1038/334124a0, 2968522.
6. Cobrinik D, Whyte P, Peeper DS, Jacks T, Weinberg RA. Cell cycle-specific association of E2F with the p130 E1A-binding domain. Genes Dev 1993, 7:2392-2404. 10.1101/gad.7.12a.2392, 8253385.
7. Li Y, Graham C, Lacy S, Duncan AM, Whyte P. The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Dev 1993, 7:2366-2377. 10.1101/gad.7.12a.2366, 8253383.
8. Hannon GJ, Demetrick D, Beach D. Isolation of the Rb-related p130 through its interaction with CDK2 and cyclins. Genes Dev 1993, 7:2378-2391. 10.1101/gad.7.12a.2378, 8253384.
9. Mayol X, Grana X, Baldi A, Sang N, Hu Q, Giordano A. Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogene 1993, 8:2561-2566.
10. Ewen ME, Xing Y, Lawrence JB, Livingston DM. Molecular cloning, chromosonal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein. Cell 1991, 66:1155-1164. 10.1016/0092-8674(91)90038-Z, 1833063.
11. Zhu L, van den Heuvel S, Helin K, Fattaey A, Ewen M, Livingston D, Dyson N, Harlow E. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. Genes Dev 1993, 7:1111-1125. 10.1101/gad.7.7a.1111, 8319904.
12. Dick FA. Structure-function analysis of the retinoblastoma tumor suppressor protein - is the whole a sum of its parts?. Cell Div 2007, 2:26. 10.1186/1747-1028-2-26, 2082274, 17854503.
13. van den Heuvel S, Dyson NJ. Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 2008, 9:713-724.
14. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2002, 2:103-112. 10.1016/S1535-6108(02)00102-2, 12204530.
15. Sherr CJ. Cancer cell cycles. Science 1996, 274:1672-1677. 10.1126/science.274.5293.1672, 8939849.
16. Horowitz JM, Park SH, Bogenmann E, Cheng JC, Yandell DW, Kaye FJ, Minna JD, Dryja TP, Weinberg RA. Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 1990, 87:2775-2779. 10.1073/pnas.87.7.2775, 53773, 2181449.
17. Wirt SE, Sage J. p107 in the public eye: an Rb understudy and more. Cell Div 2010, 5:9. 10.1186/1747-1028-5-9, 2861648, 20359370.
18. Chen D, Livne-bar I, Vanderluit JL, Slack RS, Agochiya M, Bremner R. Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma. Cancer Cell 2004, 5:539-551. 10.1016/j.ccr.2004.05.025, 15193257.
19. MacPherson D, Sage J, Kim T, Ho D, McLaughlin ME, Jacks T. Cell type-specific effects of Rb deletion in the murine retina. Genes Dev 2004, 18:1681-1694. 10.1101/gad.1203304, 478190, 15231717.
20. MacPherson D, Conkrite K, Tam M, Mukai S, Mu D, Jacks T. Murine bilateral retinoblastoma exhibiting rapid-onset, metastatic progression and N-myc gene amplification. EMBO J 2007, 26:784-794. 10.1038/sj.emboj.7601515, 1794380, 17235288.
21. Classon M, Dyson N. p107 and p130: versatile proteins with interesting pockets. Exp Cell Res 2001, 264:135-147. 10.1006/excr.2000.5135, 11237530.
22. Lee J-O, Russo AA, Pavletich NP. Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7. Nature 1998, 391:859-865. 10.1038/36038, 9495340.
23. Sellers WR, Rodgers JW, Kaelin WG. A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites. Proc Natl Acad Sci USA 1995, 92:11544-11548. 10.1073/pnas.92.25.11544, 40438, 8524800.
24. Chow KB, Starostik P, Dean DC. The Rb family contains a conserved cyclin-dependent-kinase-regulated transcriptional repressor motif. Mol Cell Biol 1996, 16:7173-7181. 231721, 8943373.
25. Chow KN, Dean DC. Domains A and B in the Rb pocket interact to form a transcriptional repressor motif. Mol Cell Biol 1996, 16:4862-4868. 231488, 8756645.
26. Hu QJ, Dyson N, Harlow E. The regions of the retinoblastoma protein needed for binding to adenovirus E1A or SV40 large T antigen are common sites for mutations. EMBO J 1990, 9:1147-1155. 551790, 2138977.
27. Dyson N, Guida P, Munger K, Harlow E. Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins. J Virol 1992, 66:6893-6902. 240306, 1331501.
28. Ewen ME, Ludlow JW, Marsilio E, DeCaprio JA, Millikan RC, Cheng SH, Paucha E, Livingston DM. An N-terminal transformation-governing sequence of SV40 large T antigen contributes to the binding of both p110Rb and a second cellular protein, p120. Cell 1989, 58:257-267. 10.1016/0092-8674(89)90840-4, 2526683.
29. Munger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. Embo J 1989, 8:4099-4105. 401588, 2556261.
30. Whyte P, Williamson NM, Harlow E. Cellular targets for transformation by the adenovirus E1A proteins. Cell 1989, 56:67-75.
31. Bremner R, Cohen BL, Sopta M, Hamel PA, Ingles CJ, Gallie BL, Phillips RA. Direct transcriptional repression by pRB and its reversal by specific cyclins. Mol Cell Biol 1995, 15:3256-3265. 230558, 7760821.
32. Hiebert SW, Chellappan SP, Horowitz JM, Nevins JR. The interaction of pRb with E2F inhibits the transcriptional activity of E2F. Genes & Dev 1992, 6:177-185. 10.1101/gad.6.2.177, 22432087.
33. Qin XQ, Chittenden T, Livingston DM, Kaelin WG. Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev 1992, 6:953-964. 10.1101/gad.6.6.953, 1534305.
34. Fattaey AR, Harlow E, Helin K. Independent regions of adenovirus E1A are required for binding to and dissociation of E2F-protein complexes. Mol Cell Biol 1993, 13:7267-7277. 364797, 8246949.
35. Sullivan CS, Cantalupo P, Pipas JM. The molecular chaperone activity of simian virus 40 large T antigen is required to disrupt Rb-E2F family complexes by an ATP-dependent mechanism. Mol Cell Biol 2000, 20:6233-6243. 10.1128/MCB.20.17.6233-6243.2000, 86098, 10938100.
36. Liu X, Marmorstein R. Structure of the retinoblastoma protein bound to adenovirus E1A reveals the molecular basis for viral oncoprotein inactivation of a tumor suppressor. Genes Dev 2007, 21:2711-2716. 10.1101/gad.1590607, 2045126, 17974914.
37. Whyte P, Ruley HE, Harlow E. Two regions of the adenovirus early region 1A proteins are required for transformation. J Virol 1988, 62:257-265. 250526, 2960834.
38. Litovchick L, Chestukhin A, DeCaprio JA. Glycogen synthase kinase 3 phosphorylates RBL2/p130 during quiescence. Mol Cell Biol 2004, 24:8970-8980. 10.1128/MCB.24.20.8970-8980.2004, 517894, 15456871.
39. Lacy S, Whyte P. Identification of a p130 domain mediating interactions with cyclin A/cdk 2 and cyclin E/cdk 2 complexes. Oncogene 1997, 14:2395-2406. 10.1038/sj.onc.1201085, 9188854.
40. Zhu L, Harlow E, Dynlacht BD. p107 uses a p21CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F. Genes Dev 1995, 9:1740-1752. 10.1101/gad.9.14.1740, 7622038.
41. Woo MS-A, Sanchez I, Dynlacht BD. p130 and p107 use a conserved domain to inhibit cellular cyclin-dependent kinase activity. Mol Cell Biol 1997, 17:3566-3579. 232210, 9199292.
42. Moberg K, Starz MA, Lees JA. E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry. Mol Cell Biol 1996, 16:1436-1449. 231128, 8657117.
43. Hurford RK, Cobrinik D, Lee MH, Dyson N. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev 1997, 11:1447-1463. 10.1101/gad.11.11.1447, 9192872.
44. Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, DeCaprio JA. Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell 2007, 26:539-551. 10.1016/j.molcel.2007.04.015, 17531812.
45. Cobrinik D. Pocket proteins and cell cycle control. Oncogene 2005, 24:2796-2809. 10.1038/sj.onc.1208619, 15838516.
46. Ciarmatori S, Scott PH, Sutcliffe JE, McLees A, Alzuherri HM, Dannenberg JH, te Riele H, Grummt I, Voit R, White RJ. Overlapping functions of the pRb family in the regulation of rRNA synthesis. Mol Cell Biol 2001, 21:5806-5814. 10.1128/MCB.21.17.5806-5814.2001, 87300, 11486020.
47. Cavanaugh AH, Hempel WM, Taylor LJ, Rogalsky V, Todorov G, Rothblum L. Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product. Nature 1995, 374:177-180. 10.1038/374177a0, 7877691.
48. Hannan KM, Hannan RD, Smith SD, Jefferson LS, Lun M, Rothblum LI. Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1. Oncogene 2000, 19:4988-4999. 10.1038/sj.onc.1203875, 11042686.
49. Scott PH, Cairns CA, Sutcliffe JE, Alzuherri HM, McLees A, Winter AG, White RJ. Regulation of RNA polymerase III transcription during cell cycle entry. J J Biol Chem 2001, 276:1005-1014.
50. White RJ, Trouche D, Martin K, Jackson SP, Kouzarides T. Repression of RNA polymerase III transcription by the retinoblastoma protein. Nature 1996, 382:88-90. 10.1038/382088a0, 8657311.
51. Ren S, Rollins BJ. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 2004, 117:239-251. 10.1016/S0092-8674(04)00300-9, 15084261.
52. Chen IT, Akamatsu M, Smith ML, Lung FD, Duba D, Roller PP, Fornace AJ, O'Connor PM. Characterization of p21Cip1/Waf1 peptide domains required for cyclin E/Cdk2 and PCNA interaction. Oncogene 1996, 12:595-607.
53. Classon M, Harlow E. The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2002, 2:910-917. 10.1038/nrc950, 12459729.
54. Chen HZ, Tsai SY, Leone G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer 2009, 9:785-797. 10.1038/nrc2696, 19851314.
55. Qin X-Q, Livingston DM, Ewen M, Sellers WR, Arany Z, Kaelin WG. The transcription factor E2F-1 is a downstream target of RB action. Mol Cell Biol 1995, 15:742-755. 231942, 7823942.
56. Johnson DG, Schwarz JK, Cress WD, Nevins JR. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 1993, 365:349-352. 10.1038/365349a0, 8377827.
57. Tsai KY, Hu Y, Macleod KF, Crowley D, Yamasaki L, Jacks T. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell 1998, 2:293-304. 10.1016/S1097-2765(00)80274-9, 9774968.
58. Ziebold U, Reza T, Caron A, Lees JA. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev 2001, 15:386-391. 10.1101/gad.858801, 312633, 11230146.
59. Saavedra HI, Wu L, de Bruin A, Timmers C, Rosol TJ, Weinstein M, Robinson ML, Leone G. Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb. Cell Growth Differ 2002, 13:215-225.
60. Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K. The retinoblastoma protein binds to a family of E2F transcription factors. Mol Cell Biol 1993, 13:7813-7825. 364853, 8246996.
61. Hijmans EM, Voorhoeve PM, Beijersbergen RL, van 't Veer L, Bernards R. E2F-5, a new E2F family member that interacts with p130 in vivo. Mol Cell Biol 1995, 15:3082-3089. 230539, 7760804.
62. Beijersbergen RL, Kerkhoven RM, Zhu L, Carlee L, Voorhoeve PM, Bernards RE. E2F-4, a new member of the E2F gene family, has oncogenic activity and associates with p107 in vivo. Genes Dev 1994, 8:2680-2690. 10.1101/gad.8.22.2680, 7958925.
63. Ginsberg D, Vairo G, Chittenden T, Xiao ZX, Xu G, Wydner KL, DeCaprio JA, Lawrence JB, Livingston DM. E2F-4, a new member of the E2F transcription factor family, interacts with p107. Genes Dev 1994, 8:2665-2679. 10.1101/gad.8.22.2665, 7958924.
64. Dimova DK, Dyson NJ. The E2F transcriptional network: old acquaintances with new faces. Oncogene 2005, 24:2810-2826. 10.1038/sj.onc.1208612, 15838517.
65. Macaluso M, Montanari M, Giordano A. Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes. Oncogene 2006, 25:5263-5267. 10.1038/sj.onc.1209680, 16936746.
66. Wells J, Boyd K, Fry C, Bartley S, Farnham P. Target gene specificity of E2F and pocket protein family members in living cells. Mol Cell Biol 2000, 20:5797-5807. 10.1128/MCB.20.16.5797-5807.2000, 86057, 10913163.
67. Takahashi Y, Rayman J, Dynlacht B. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev 2000, 14:804-816. 316494, 10766737.
68. Helin K, Harlow E, Fattaey A. Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein. Mol Cell Biol 1993, 13:6501-6508. 364709, 8413249.
69. Flemington EK, Speck SH, Kaelin WG. E2F-1 mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Natl Acad Sci USA 1993, 90:6914-6918. 10.1073/pnas.90.15.6914, 47045, 8346196.
70. Zamanian M, Thangue NBL. Transcriptional repression by the Rb-related protein p107. Mol Biol Cell 1993, 4:389-396. 300940, 7685208.
71. Mulligan GJ, Wong J, Jacks T. p130 is dispensable in peripheral T lymphocytes: evidence for functional compensation by p107 and p130. Mol Cell Biol 1998, 18:206-220. 121478, 9418868.
72. Dagnino L, Zhu L, Skorecki KL, Moses HL. E2F-independent transcriptional repression by p107, a member of the retinoblastoma family of proteins. Cell Growth Differ 1995, 6:191-198.
73. Lavia P, Jansen-Durr P. E2F target genes and cell-cycle checkpoint control. Bioessays 1999, 21:221-230. 10.1002/(SICI)1521-1878(199903)21:3<221::AID-BIES6>3.0.CO;2-J, 10333731.
74. Williams JP, Stewart T, Li B, Mulloy R, Dimova D, Classon M. The retinoblastoma protein is required for Ras-induced oncogenic transformation. Mol Cell Biol 2006, 26:1170-1182. 10.1128/MCB.26.4.1170-1182.2006, 1367176, 16449633.
75. Isaac CE, Francis SM, Martens AL, Julian LM, Seifried LA, Erdmann N, Binne UK, Harrington L, Sicinski P, Berube NG, et al. The retinoblastoma protein regulates pericentric heterochromatin. Mol Cell Biol 2006, 26:3659-3671. 10.1128/MCB.26.9.3659-3671.2006, 1447412, 16612004.
76. Francis SM, Bergsied J, Isaac CE, Coschi CH, Martens AL, Hojilla CV, Chakrabarti S, Dimattia GE, Khoka R, Wang JY, Dick FA. A functional connection between pRB and transforming growth factor beta in growth inhibition and mammary gland development. Mol Cell Biol 2009, 29:4455-4466. 10.1128/MCB.00473-09, 2725731, 19506017.
77. Mittnacht S. Control of pRB phosphorylation. Curr Opin Genet Dev 1998, 8:21-27. 10.1016/S0959-437X(98)80057-9, 9529601.
78. Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell 2008, 14:159-169. 10.1016/j.devcel.2008.01.013, 18267085.
79. Sherr C, Roberts J. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999, 13:1501-1512. 10.1101/gad.13.12.1501, 10385618.
80. Mateyak MK, Obaya AJ, Sedivy JM. c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol 1999, 19:4672-4683. 84265, 10373516.
81. Yang W, Shen J, Wu M, Arsura M, FitzGerald M, Suldan Z, Kim DW, Hofmann CS, Pianetti S, Romieu-Mourez R, et al. Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 2001, 20:1688-1702. 10.1038/sj.onc.1204245, 11313917.
82. Howe JA, Bayley S. Effects of Ad5 E1A mutant viruses on the cell cycle in relation to the binding of cellular proteins including the retinoblastoma protein and cyclin A. Virol 1992, 186:15-24.
83. Faha B, Ewen ME, Tsai LH, Livingston DM, Harlow E. Interaction between human cyclin A and adenovirus E1A-associated p107 protein. Science 1992, 255:87-90. 10.1126/science.1532458, 1532458.
84. Ewen ME, Faha B, Harlow E, Livingston DM. Interaction of p107 with cyclin A independent of complex formation with viral oncoproteins. Science 1992, 255:85-87. 10.1126/science.1532457, 1532457.
85. Hauser P, Agrawal D, Chu B, Pledger W. p107 and p130 associated cyclin A has altered substrate specificity. J Biol Chem 1997, 272:22954-22959. 10.1074/jbc.272.36.22954, 9278460.
86. Castano E, Kleyner Y, Dynlacht B. Dual cyclin-binding domains are required for p107 to function as a kinase inhibitor. Mol Cell Biol 1998, 18:5380-5391. 109123, 9710622.
87. Howard CM, Claudio PP, De Luca A, Stiegler P, Jori FP, Safdar NM, Caputi M, Khalili K, Giordano A. Inducible pRb2/p130 expression and growth-suppressive mechanisms: evidence of a pRb2/p130, p27Kip1, and cyclin E negative feedback regulatory loop. Cancer Res 2000, 60:2737-2744.
88. Ji P, Jiang H, Rekhtman K, Bloom J, Ichetovkin M, Pagano M, Zhu L. An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. Mol Cell 2004, 16:47-58. 10.1016/j.molcel.2004.09.029, 15469821.
89. Binne UK, Classon MK, Dick FA, Wei W, Rape M, Kaelin WG, Naar AM, Dyson NJ. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol 2007, 9:225-232. 10.1038/ncb1532, 17187060.
90. Rodier G, Makris C, Coulombe P, Scime A, Nakayama K, Nakayama KI, Meloche S. p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2. J Cell Biol 2005, 168:55-66. 2171673, 15631990.
91. Sangwan M, McCurdy SR, Livne-Bar I, Ahmad M, Wrana JL, Chen D, Bremner R. Established and new mouse models reveal E2f1 and Cdk2 dependency of retinoblastoma, and expose effective strategies to block tumor initiation. Oncogene 2012,
92. Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev 1998, 12:2245-2262. 10.1101/gad.12.15.2245, 9694791.
93. Le Cam L, Polanowska J, Fabbrizio E, Olivier M, Philips A, Ng Eaton E, Classon M, Geng Y, Sardet C. Timing of cyclin E gene expression depends on the regulated association of a bipartite repressor element with a novel E2F complex. EMBO J 1999, 18:1878-1890. 10.1093/emboj/18.7.1878, 1171273, 10202151.
94. Verona R, Moberg K, Estes S, Starz M, Vernon JP, Lees JA. E2F Activity is regulated by cell-cycle-dependent changes in subcellular localization. Mol Cell Biol 1997, 17:7268-7282. 232584, 9372959.
95. Chestukhin A, Litovchick L, Rudich K, DeCaprio JA. Nucleocytoplasmic shuttling of p130/RBL2: novel regulatory mechanism. Mol Cell Biol 2002, 22:453-468. 10.1128/MCB.22.2.453-468.2002, 139733, 11756542.
96. Tedesco D, Lukas J, Reed SI. The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2). Genes Dev 2002, 16:2946-2957. 10.1101/gad.1011202, 187481, 12435635.
97. Yao G, Lee TJ, Mori S, Nevins JR, You L. A bistable Rb-E2F switch underlies the restriction point. Nature Cell Biol 2008, 10:476-482. 10.1038/ncb1711, 18364697.
98. Adams PD, Li X, Sellers WR, Baker KB, Leng X, Harper JW, Taya Y, Kaelin WG. Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol Cell Biol 1999, 19:1068-1080. 116037, 9891042.
99. Knudsen ES, Wang JY. Dual mechanisms for the inhibition of E2F binding to RB by cyclin-dependent kinase-mediated RB phosphorylation. Mol Cell Biol 1997, 17:5771-5783. 232425, 9315635.
100. Brown VD, Phillips RA, Gallie BL. Cumulative effect of phosphorylation of pRB on regulation of E2F activity. Mol Cell Biol 1999, 19:3246-3256. 84119, 10207050.
101. Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol 1998, 18:753-761. 108786, 9447971.
102. PhosphositePlus. , http://www.phosphosite.org/homeAction.do
103. Frolov MV, Dyson NJ. Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J Cell Sci 2004, 117:2173-2181. 10.1242/jcs.01227, 15126619.
104. Calbo J, Parreno M, Sotillo E, Yong T, Mazo A, Garriga J, Grana X. G1 cyclin/cyclin-dependent kinase-coordinated phosphorylation of endogenous pocket proteins differentially regulates their interactions with E2F4 and E2F1 and gene expression. J Biol Chem 2002, 277:50263-50274. 10.1074/jbc.M209181200, 12401786.
105. Ianari A, Natale T, Calo E, Ferretti E, Alesse E, Screpanti I, Haigis K, Gulino A, Lees JA. Proapoptotic function of the retinoblastoma tumor suppressor protein. Cancer Cell 2009, 15:184-194. 10.1016/j.ccr.2009.01.026, 2880703, 19249677.
106. Wells J, Yan PS, Cechvala M, Huang T, Farnham PJ. Identification of novel pRb binding sites using CpG microarrays suggests that E2F recruits pRb to specific genomic sites during S phase. Oncogene 2003, 22:1445-1460. 10.1038/sj.onc.1206264, 12629508.
107. Dick FA, Dyson N. pRB contains an E2F1-specific binding domain that allows E2F1-induced apoptosis to be regulated separately from other E2F activities. Mol Cell 2003, 12:639-649. 10.1016/S1097-2765(03)00344-7, 14527410.
108. Cecchini MJ, Dick FA. The biochemical basis of CDK phosphorylation-independent regulation of E2F1 by the retinoblastoma protein. Biochem J 2011, 434:297-308. 10.1042/BJ20101210, 21143199.
109. Knudsen KE, Booth D, Naderi S, Sever-Chroneos Z, Fribourg AF, Hunton IC, Feramisco JR, Wang JY, Knudsen ES. RB-dependent S-phase response to DNA damage. Mol Cell Biol 2000, 20:7751-7763. 10.1128/MCB.20.20.7751-7763.2000, 86358, 11003670.
110. Karantza V, Maroo A, Fay D, Sedivy JM. Overproduction of Rb protein after the G1/S boundary causes G2 arrest. Mol Cell Biol 1993, 13:6640-6652. 364727, 8413260.
111. Sever-Chroneos Z, Angus SP, Fribourg AF, Wan H, Todorov I, Knudsen KE, Knudsen ES. Retinoblastoma tumor suppressor protein signals through inhibition of cyclin-dependent kinase 2 activity to disrupt PCNA function in S phase. Mol Cell Biol 2001, 21:4032-4045. 10.1128/MCB.21.12.4032-4045.2001, 87065, 11359910.
112. Avni D, Yang H, Martelli F, Hofmann F, ElShamy WM, Ganesan S, Scully R, Livingston DM. Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage. Mol Cell 2003, 12:735-746. 10.1016/S1097-2765(03)00355-1, 14527418.
113. Markham D, Munro S, Soloway J, O'Connor DP, La Thangue NB. DNA-damage-responsive acetylation of pRb regulates binding to E2F-1. EMBO Rep 2006, 7:192-198. 10.1038/sj.embor.7400591, 1369245, 16374512.
114. Broceno C, Wilkie S, Mittnacht S. RB activation defect in tumor cell lines. Proc Natl Acad Sci USA 2002, 99:14200-14205. 10.1073/pnas.212519499, 137861, 12379745.
115. Chan HM, Krstic-Demonacos M, Smith L, Demonacos C, La Thangue NB. Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Genet 2001, 3:667-674.
116. Hernando E, Nahle Z, Juan G, Diaz-Rodriguez E, Alaminos M, Hemann M, Michel L, Mittal V, Gerald W, Benezra R, et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 2004, 430:797-802. 10.1038/nature02820, 15306814.
117. Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD, Jackson PK. Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev Cell 2003, 4:813-826. 10.1016/S1534-5807(03)00153-9, 12791267.
118. Niculescu AB, Chen X, Smeets M, Hengst L, Prives C, Reed SI. Effects of p21 Cip1/Waf1 at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol 1998, 18:629-643. 121530, 9418909.
119. Srinivasan SV, Mayhew CN, Schwemberger S, Zagorski W, Knudsen ES. RB loss promotes aberrant ploidy by deregulating levels and activity of DNA replication factors. J Biol Chem 2007, 282:23867-23877. 10.1074/jbc.M700542200, 17556357.
120. Gonzalo S, Garcia-Cao M, Fraga MF, Schotta G, Peters AH, Cotter SE, Eguia R, Dean DC, Esteller M, Jenuwein T, Blasco MA. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 2005, 7:420-428. 10.1038/ncb1235, 15750587.
121. Longworth MS, Herr A, Ji JY, Dyson NJ. RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes Dev 2008, 22:1011-1024. 10.1101/gad.1631508, 2335323, 18367646.
122. Manning AL, Longworth MS, Dyson NJ. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev 2010, 24:1364-1376. 10.1101/gad.1917310, 2895196, 20551165.
123. Coschi CH, Martens AL, Ritchie K, Francis SM, Chakrabarti S, Berube NG, Dick FA. Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive. Genes Dev 2010, 24:1351-1363. 10.1101/gad.1917610, 2895195, 20551166.
124. van Harn T, Foijer F, van Vugt M, Banerjee R, Yang F, Oostra A, Joenje H, te Riele H. Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev 2010, 24:1377-1388. 10.1101/gad.580710, 2895197, 20551164.
125. Nelson DA, Krucher NA, Ludlow JW. High molecular weight protein phosphatase type 1 dephosphorylates the retinoblastoma protein. J Biol Chem 1997, 272:4528-4535. 10.1074/jbc.272.7.4528, 9020179.
126. Yan Y, Mumby MC. Distinct roles for PP1 and PP2A in phosphorylation of the retinoblastoma protein. PP2a regulates the activities of G(1) cyclin-dependent kinases. J Biol Chem 1999, 274:31917-31924. 10.1074/jbc.274.45.31917, 10542219.
127. Cicchillitti L, Fasanaro P, Biglioli P, Capogrossi MC, Martelli F. Oxidative stress induces protein phosphatase 2A-dependent dephosphorylation of the pocket proteins pRb, p107, and p130. J Biol Chem 2003, 278:19509-19517. 10.1074/jbc.M300511200, 12621062.
128. Hirschi A, Cecchini M, Steinhardt RC, Schamber MR, Dick FA, Rubin SM. An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein. Nat Struct Mol Biol 2010, 17:1051-1057. 10.1038/nsmb.1868, 2933323, 20694007.
129. Durfee T, Becherer K, Chen P-L, Yeh S-H, Yang Y, Kilburn AE, Lee W-H, Elledge SJ. The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes Dev 1993, 7:555-569. 10.1101/gad.7.4.555, 8384581.
130. Dunaief JL, King A, Esumi N, Eagen M, Dentchev T, Sung CH, Chen S, Zack DJ. Protein Phosphatase 1 binds strongly to the retinoblastoma protein but not to p107 or p130 in vitro and in vivo. Curr Eye Res 2002, 24:392-396. 10.1076/ceyr.24.5.392.8524, 12434308.
131. Garriga J, Jayaraman AL, Limon A, Jayadeva G, Sotillo E, Truongcao M, Patsialou A, Wadzinski BE, Grana X. A dynamic equilibrium between CDKs and PP2A modulates phosphorylation of pRB, p107 and p130. Cell Cycle 2004, 3:1320-1330. 10.4161/cc.3.10.1183, 15467457.
132. Massague J. TGFbeta in cancer. Cell 2008, 134:215-230. 10.1016/j.cell.2008.07.001, 18662538.
133. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-b-induced cell cycle arrest. Nature 1994, 371:257-261. 10.1038/371257a0, 8078588.
134. Liu W, Wu G, Li W, Lobur D, Wan Y. Cdh1-anaphase-promoting complex targets Skp2 for destruction in transforming growth factor beta-induced growth inhibition. Mol Cell Biol 2007, 27:2967-2979. 10.1128/MCB.01830-06, 1899917, 17283060.
135. Siegel PM, Massague J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 2003, 3:807-821. 10.1038/nrc1208, 14557817.
136. Chen CR, Kang Y, Siegel PM, Massague J. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 2002, 110:19-32. 10.1016/S0092-8674(02)00801-2, 12150994.
137. Mukherjee P, Winter SL, Alexandrow MG. Cell cycle arrest by transforming growth factor beta1 near G1/S is mediated by acute abrogation of prereplication complex activation involving an Rb-MCM interaction. Mol Cell Biol 2010, 30:845-856. 10.1128/MCB.01152-09, 2812244, 19948884.
138. Bruce JL, Hurford RKJ, Classon M, Koh J, Dyson N. Requirements for cell cycle arrest by p16INK4a. Mol Cell 2000, 6:737-742. 10.1016/S1097-2765(00)00072-1, 11030353.
139. Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007, 8:729-740.
140. Sage J, Mulligan G, Attardi L, Miller A, Chen S, Williams B, Theodorou E, Jacks T. Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalization. Genes Dev 2000, 14:3037-3050. 10.1101/gad.843200, 317090, 11114892.
141. Dannenberg J-H, van Rossum A, Schuijff L, te Riele H. Ablation of the Retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev 2000, 14:3051-3064. 10.1101/gad.847700, 317114, 11114893.
142. Peeper D, Dannenberg J, Douma S, teRiele H, Bernards R. Escape from premature senescence is not sufficient for oncogenic transformation by ras. Nat Cell Biol 2001, 198-203.
143. Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 2003, 424:223-228. 10.1038/nature01764, 12853964.
144. Brehm A, Kouzarides T. Retinoblastoma protein meets chromatin. TIBS 1999, 24:142-145.
145. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 2000, 25:338-342. 10.1038/77124, 10888886.
146. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 1998, 391:597-601. 10.1038/35404, 9468139.
147. Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J, Begemann M, Crabtree GR, Goff SP. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 1994, 79:119-130. 10.1016/0092-8674(94)90405-7, 7923370.
148. Luo RX, Postigo AA, Dean DC. Rb interacts with histone deacetylase to repress transcription. Cell 1998, 92:463-473. 10.1016/S0092-8674(00)80940-X, 9491888.
149. Magnaghi L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP, Troalen F, Trouche D, Harel-Bellan A. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 1998, 391:601-604. 10.1038/35410, 9468140.
150. Vandel L, Nicolas E, Vaute O, Ferreira R, Ait-Si-Ali S, Trouche D. Transcriptional repression by the retinoblastoma protein through the recruitment of a histone methyltransferase. Mol Cell Biol 2001, 21:6484-6494. 10.1128/MCB.21.19.6484-6494.2001, 99795, 11533237.
151. Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, O'Carroll D, Firestein R, Cleary M, Jenuwein T, Herrera RE, Kouzarides T. Rb targets histone H3 methylation and HP1 to promoters. Nature 2001, 412:561-565. 10.1038/35087620, 11484059.
152. Morrison AJ, Sardet C, Herrera RE. Retinoblastoma protein transcriptional repression through histone deacetylation of a single nucleosome. Mol Cell Biol 2002, 22:856-865. 10.1128/MCB.22.3.856-865.2002, 133558, 11784861.
153. Blais A, Dynlacht BD. E2F-associated chromatin modifiers and cell cycle control. Curr Opin Cell Biol 2007, 19:658-662. 10.1016/j.ceb.2007.10.003, 18023996.
154. Chicas A, Wang X, Zhang C, McCurrach M, Zhao Z, Mert O, Dickins RA, Narita M, Zhang M, Lowe SW. Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 2010, (17):376-387.
155. Talluri S, Isaac CE, Ahmad M, Henley SA, Francis SM, Martens AL, Bremner R, Dick FA. A G1 checkpoint mediated by the retinoblastoma protein that is dispensable in terminal differentiation but essential for senescence. Mol Cell Biol 2010, 30:948-960. 10.1128/MCB.01168-09, 2815577, 20008551.
156. Vernier M, Bourdeau V, Gaumont-Leclerc MF, Moiseeva O, Begin V, Saad F, Mes-Masson AM, Ferbeyre G. Regulation of E2Fs and senescence by PML nuclear bodies. Genes Dev 2011, 25:41-50. 10.1101/gad.1975111, 3012935, 21205865.
157. Stiegler P, De Luca A, Bagella L, Giordano A. The COOH-terminal region of pRb2/p130 binds to histone deacetylase 1 (HDAC1), enhancing transcriptional repression of the E2F-depedent cyclin A promoter. Cancer Res 1998, 58:5049-5052.
158. Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D. The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase. Proc Natl Acad Sci USA 1998, 95:10493-10498. 10.1073/pnas.95.18.10493, 27922, 9724731.
159. Shamma A, Takegami Y, Miki T, Kitajima S, Noda M, Obara T, Okamoto T, Takahashi C. Rb Regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation. Cancer Cell 2009, 15:255-269. 10.1016/j.ccr.2009.03.001, 19345325.
160. Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev 2011, 25:801-813. 10.1101/gad.2034211, 3078706, 21498570.
161. Tschop K, Conery AR, Litovchick L, DeCaprio JA, Settleman J, Harlow E, Dyson N. A kinase shRNA screen links LATS2 and pRB tumor suppressor. Genes Dev 2011, 25:814-830. 10.1101/gad.2000211, 3078707, 21498571.
162. Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003, 113:703-716. 10.1016/S0092-8674(03)00401-X, 12809602.
163. Zhang R, Chen W, Adams PD. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol 2007, 27:2343-2358. 10.1128/MCB.02019-06, 1820509, 17242207.
164. Funayama R, Saito M, Tanobe H, Ishikawa F. Loss of linker histone H1 in cellular senescence. J Cell Biol 2006, 175:869-880. 10.1083/jcb.200604005, 2064697, 17158953.
165. Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 2005, 8:19-30. 10.1016/j.devcel.2004.10.019, 15621527.