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Molecular Biology of Retinoblastoma

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Part of the Essentials in Ophthalmology book series (ESSENTIALS)

Abstract

The molecular biology of retinoblastoma has led to a revolution in our understanding of cancer biology. This chapter reviews the discovery and subsequent elucidation of RB1, the first tumor suppressor gene, and its protein product, Rb. The Rb pathway plays a key regulatory role in gene transcription, cell cycle regulation, cellular differentiation, apoptosis, and the maintenance of chromosomal stability. This critical tumor suppressor pathway is disrupted in the vast majority of human cancers; thus retinoblastoma has had a far-reaching impact on cancer research that far exceeds its clinical prevalence. New discoveries will continue to emerge from the study of retinoblastoma and the Rb pathway, and these will likely play an important role in the continued search for better cancer therapies.

Keywords

Retinoblastoma Eye cancer Tumor suppressor gene Cell cycle Differentiation Apoptosis 

Notes

Compliance with Ethical Requirements

Conflict of Interest

Scott D. Walter, M.D., M.Sc. and J. William Harbour, M.D. declare that they have no conflict of interest.

No human or animal studies were carried out by the authors for this article.

References

  1. Abouzeid H, Schorderet DF, Balmer A, et al. Germline mutations in retinoma patients: relevance to low-penetrance and low-expressivity molecular basis. Mol Vis. 2009;15:771–7.PubMedCentralPubMedGoogle Scholar
  2. Abramson DH, Dunkel IJ, Brodie SE, et al. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology. 2010;117:1623–9.PubMedCrossRefGoogle Scholar
  3. Anwar SL, Krech T, Hasemeier B, et al. Deregulation of RB1 expression by loss of imprinting in human hepatocellular carcinoma. J Pathol. 2014;233:392–401.PubMedCrossRefGoogle Scholar
  4. Arnold A. The cyclin D1/PRAD1 oncogene in human neoplasia. J Investig Med. 1995;43:543–9.PubMedGoogle Scholar
  5. Benedict WF, Murphree AL, Banerjee A, et al. Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene. Science. 1983;219:973–5.PubMedCrossRefGoogle Scholar
  6. Bester AC, Roniger M, Oren YS, et al. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell. 2011;145:435–46.PubMedCentralPubMedCrossRefGoogle Scholar
  7. Bignell GR, Greenman CD, Davies H, et al. Signatures of mutation and selection in the cancer genome. Nature. 2010;463:893–8.PubMedCentralPubMedCrossRefGoogle Scholar
  8. Blach LE, McCormick B, Abramson DH, et al. Trilateral retinoblastoma—incidence and outcome: a decade of experience. Int J Radiat Oncol Biol Phys. 1994;29:729–33.PubMedCrossRefGoogle Scholar
  9. Blanquet V, Turleau C, de Grouchy J, et al. Physical map around the retinoblastoma gene: possible genomic imprinting suggested by NruI digestion. Genomics. 1991;10:350–5.PubMedCrossRefGoogle Scholar
  10. Brantley Jr MA, Harbour JW. Inactivation of retinoblastoma protein in uveal melanoma by phosphorylation of sites in the COOH-terminal region. Cancer Res. 2000;60:4320–3.PubMedGoogle Scholar
  11. Brehm A, Miska EA, McCance DJ, et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature. 1998;391:597–601.PubMedCrossRefGoogle Scholar
  12. Cavenee WK, Dryja TP, Phillips RA, et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature. 1983;305:779–84.PubMedCrossRefGoogle Scholar
  13. Chellappan SP, Hiebert S, Mudryj M, et al. The E2F transcription factor is a cellular target for the RB protein. Cell. 1991;65:1053–61.PubMedCrossRefGoogle Scholar
  14. Chen PL, Riley DJ, Chen Y, et al. Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs. Genes Dev. 1996a;10:2794–804.PubMedCrossRefGoogle Scholar
  15. Chen PL, Riley DJ, Chen-Kiang S, et al. Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6. Proc Natl Acad Sci U S A. 1996b;93:465–9.PubMedCentralPubMedCrossRefGoogle Scholar
  16. Chen PL, Scully P, Shew JY, et al. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell. 1989;58:1193–8.PubMedCrossRefGoogle Scholar
  17. Chong JL, Wenzel PL, Sáenz-Robles MT, et al. E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature. 2009;462:930–4.PubMedCentralPubMedCrossRefGoogle Scholar
  18. Chow KN, Dean DC. Domains A and B in the Rb pocket interact to form a transcriptional repressor motif. Mol Cell Biol. 1996;16:4862–8.PubMedCentralPubMedCrossRefGoogle Scholar
  19. Christensen J, Agger K, Cloos PA. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 2007;128:1063–76.PubMedCrossRefGoogle Scholar
  20. Coschi CH, Martens AL, Ritchie K, et al. Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive. Genes Dev. 2010;24:1351–63.PubMedCentralPubMedCrossRefGoogle Scholar
  21. Dahiya A, Wong S, Gonzalo S, et al. Linking the Rb and polycomb pathways. Mol Cell. 2001;8:557–69.PubMedCrossRefGoogle Scholar
  22. DeCaprio JA, Ludlow JW, Figge J, et al. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell. 1988;54:275–83.PubMedCrossRefGoogle Scholar
  23. DeCaprio JA, Furukawa Y, Ajchenbaum F, et al. The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression. Proc Natl Acad Sci U S A. 1992;89:1795–8.PubMedCentralPubMedCrossRefGoogle Scholar
  24. DeCaprio JA, Ludlow JW, Lynch D, et al. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell. 1989;58:1085–95.PubMedCrossRefGoogle Scholar
  25. DeGregori JA, Johnson DG. Distinct and overlapping roles for e2f family members in transcription, proliferation and apoptosis. Curr Mol Med. 2006;6:739–48.PubMedGoogle Scholar
  26. Dehainault C, Garancher A, Castéra L, et al. The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion. Hum Mol Genet. 2014;23:5243–50.PubMedCrossRefGoogle Scholar
  27. de Jong MC, Kors WA, de Graf P, Castelijns JA, Kivela T, Moll AC. Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol. 2014;15(10):1157–67.PubMedCrossRefGoogle Scholar
  28. Delston RB, Harbour JW. Rb at the interface between cell cycle and apoptotic decisions. Curr Mol Med. 2006;6:713–8.PubMedGoogle Scholar
  29. Dyson N, Howley PM, Munger K, et al. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989;243:934–7.PubMedCrossRefGoogle Scholar
  30. Elison JR, Cobrinik D, Claros N, et al. Small molecule inhibition of HDM2 leads to p53-mediated cell death in retinoblastoma cells. Arch Ophthalmol. 2006;124:1269–75.PubMedCrossRefGoogle Scholar
  31. Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993;85:1121–8.PubMedCrossRefGoogle Scholar
  32. Ewen ME, Sluss HK, Sherr CJ, et al. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993;73:487–97.PubMedCrossRefGoogle Scholar
  33. Ferrari R, Pellegrini M, Horwitz GA, et al. Epigenetic reprogramming by adenovirus e1a. Science. 2008;321:1086–8.PubMedCentralPubMedCrossRefGoogle Scholar
  34. Flemington EK, Speck SH, Kaelin WJ. E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A. 1993;90:6914–8.PubMedCentralPubMedCrossRefGoogle Scholar
  35. Franke U. Retinoblastoma and chromosome 13. Cytogenet Cell Genet. 1976;16:131–4.CrossRefGoogle Scholar
  36. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643–6.PubMedCrossRefGoogle Scholar
  37. Gallie BL, Ellsworth RM, Abramson DH, et al. Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer. 1982;45:513–21.PubMedCentralPubMedCrossRefGoogle Scholar
  38. Geahlen RL. Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends Pharmacol Sci. 2014;35:414–22.PubMedCentralPubMedCrossRefGoogle Scholar
  39. Goodrich DW, Wang NP, Qian YW, et al. The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell. 1991;67:293–302.PubMedCrossRefGoogle Scholar
  40. Gratias S, Rieder H, Ullmann R, et al. Allelic loss in a minimal region on chromosome 16q24 is associated with vitreous seeding of retinoblastoma. Cancer Res. 2007;67:408–16.PubMedCrossRefGoogle Scholar
  41. Greger V, Passarge E, Höpping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet. 1989;83(2):155–8.PubMedCrossRefGoogle Scholar
  42. Gu W, Schneider JW, Condorelli G, et al. Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell. 1993;72:309–24.PubMedCrossRefGoogle Scholar
  43. Gustmann S, Klein-Hitpass L, Stephan H, et al. Loss at chromosome arm 16q in retinoblastoma: confirmation of the association with diffuse vitreous seeding and refinement of the recurrently deleted region. Genes Chromosomes Cancer. 2011;50:327–37.PubMedCrossRefGoogle Scholar
  44. Harbour JW. Molecular basis of low-penetrance retinoblastoma. Arch Ophthalmol. 2001a;119:1699–704.PubMedCrossRefGoogle Scholar
  45. Harbour JW. Overview of RB gene mutations in patients with retinoblastoma. Implications for clinical genetic screening. Ophthalmology. 1998;105:1442–7.PubMedCrossRefGoogle Scholar
  46. Harbour JW. Retinoblastoma: treatment. In: Char DH, editor. Tumors of the eye and orbit. Philadelphia: BC Decker; 2001b. p. 266–78.Google Scholar
  47. Harbour JW. Retinoblastoma: pathogenesis and diagnosis. In: Char DH, editor. Tumors of the eye and orbit. Philadelphia: BC Decker; 2001c. p. 253–65.Google Scholar
  48. Harbour JW, Dean DC. Rb function in cell-cycle regulation and apoptosis. Nat Cell Biol. 2000a;2:E65–7.PubMedCrossRefGoogle Scholar
  49. Harbour JW, Dean DC. The Rb/E2F pathway: emerging paradigms and expanding roles. Genes Dev. 2000b;14:2545–62.CrossRefGoogle Scholar
  50. Harbour JW, Dean DC. Chromatin remodeling and Rb activity. Curr Opin Cell Biol. 2000c;12:685–9.PubMedCrossRefGoogle Scholar
  51. Harbour JW, Lai SL, Whang-Peng J, et al. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science. 1988;241:353–7.PubMedCrossRefGoogle Scholar
  52. Harbour JW, Luo RX, Dei Sante A, et al. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999;98:859–69.PubMedCrossRefGoogle Scholar
  53. Harbour JW, Murray TG, Hamasaki D, et al. Local carboplatin therapy in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci. 1996;37:1892–8.PubMedGoogle Scholar
  54. Helin K, Harlow E, Fattaey A. Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein. Mol Cell Biol. 1993;13:6501–8.PubMedCentralPubMedCrossRefGoogle Scholar
  55. Hiebert SW. 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. 1993;13:3384–91.PubMedCentralPubMedCrossRefGoogle Scholar
  56. Hinds PW, Mittnacht S, Dulic V, et al. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992;70:993–1006.PubMedCrossRefGoogle Scholar
  57. Hume AJ, Finkel JS, Kamil JP, et al. Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function. Science. 2008;320:797–9.PubMedCrossRefGoogle Scholar
  58. Hsieh JK, Chan FS, O’Connor DJ, et al. RB regulates the stability and the apoptotic function of p53 via MDM2. Mol Cell. 1999;3:181–93.PubMedCrossRefGoogle Scholar
  59. Ikeda MA, Jakoi L, Nevins JR. A unique role for the Rb protein in controlling E2F accumulation during cell growth and differentiation. Proc Natl Acad Sci U S A. 1996;93:3215–20.PubMedCentralPubMedCrossRefGoogle Scholar
  60. Kanber D, Berulava T, Ammerpohl O, et al. The human retinoblastoma gene is imprinted. PLoS Genet. 2009;5(12):e1000790. doi: 10.1371/journal.pgen.1000790.PubMedCentralPubMedCrossRefGoogle Scholar
  61. Kato MV, Shimizu T, Ishizaki K, et al. Loss of heterozygosity on chromosome 17 and mutation of the p53 gene in retinoblastoma. Cancer Lett. 1996;106:75–82.PubMedCrossRefGoogle Scholar
  62. Klose RJ, Yan Q, Tothova Z, et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell. 2007;128:889–900.PubMedCrossRefGoogle Scholar
  63. Knudson Jr AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68:820–3.PubMedCentralPubMedCrossRefGoogle Scholar
  64. Lasorella A, Noseda M, Beyna M, et al. Id2 is a retinoblastoma protein target and mediates signaling by Myc oncoproteins. Nature. 2000;407:592–8.PubMedCrossRefGoogle Scholar
  65. Laurie NA, Donovan SL, Shih CS, et al. Inactivation of the p53 pathway in retinoblastoma. Nature. 2006;444:61–6.PubMedCrossRefGoogle Scholar
  66. Laurie NA, Shih CS, Dyer MA. Targeting MDM2 and MDMX in retinoblastoma. Curr Cancer Drug Targets. 2007;7:689–95.PubMedCrossRefGoogle Scholar
  67. Lee EY, Hu N, Yuan SS, et al. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev. 1994;8:2008–21.PubMedCrossRefGoogle Scholar
  68. Lee WH, Shew JY, Hong FD, et al. The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature. 1987;329:642–5.PubMedCrossRefGoogle Scholar
  69. Luo RX, Postigo AA, Dean DC. Rb interacts with histone deacetylase to repress transcription. Cell. 1998;92:463–73.PubMedCrossRefGoogle Scholar
  70. Ma D, Zhou P, Harbour JW. Distinct mechanisms for regulating the tumor suppressor and antiapoptotic functions of Rb. J Biol Chem. 2003;278:19358–66.PubMedCrossRefGoogle Scholar
  71. Magnaghi JL, Groisman R, Naguibneva I, et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature. 1998;391:601–5.CrossRefGoogle Scholar
  72. Mancini D, Singh S, Ainsworth P, et al. Constitutively methylated CpG dinucleotides as mutation hot spots in the retinoblastoma gene (RB1). Am J Hum Genet. 1997;61:80–7.PubMedCentralPubMedCrossRefGoogle Scholar
  73. Manning AL, Longworth MS, Dyson NJ. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev. 2010;24:1364–76.PubMedCentralPubMedCrossRefGoogle Scholar
  74. Marcus DM, Brooks SE, Leff G, et al. Trilateral retinoblastoma: insights into histogenesis and management. Surv Ophthalmol. 1998;43:59–70.PubMedCrossRefGoogle Scholar
  75. Margo C, Hidayat A, Kopelman J. Retinocytoma: a benign variant of retinoblastoma. Arch Ophthalmol. 1983;101:1519–31.PubMedCrossRefGoogle Scholar
  76. Moll AC, Imhof SM, Bouter LM, et al. Second primary tumors in patients with retinoblastoma. A review of the literature. Ophthalmic Genet. 1997;18:27–34.PubMedCrossRefGoogle Scholar
  77. Morris EJ, Ji JY, Yang F, et al. E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature. 2008;455:552–56.Google Scholar
  78. Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous seeding in retinoblastoma: recent advances and perspectives. Saudi J Ophthalmol. 2013;27:147–50.PubMedCentralPubMedCrossRefGoogle Scholar
  79. Neel JV, Falls HF. The rate of mutation of the gene responsible for retinoblastoma in man. Science. 1951;114:419–22.PubMedCrossRefGoogle Scholar
  80. Nielsen SJ, Schneider R, Bauer UM, et al. Rb targets histone H3 methylation and HP1 to promoters. Nature. 2001;412:561–5.PubMedCrossRefGoogle Scholar
  81. Noorani HZ, Khan HN, Gallie BL, et al. Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma. Am J Hum Genet. 1996;59:301–7.PubMedCentralPubMedGoogle Scholar
  82. Okamoto A, Demetrick DJ, Spillare EA, et al. Mutations and altered expression of p16INK4 in human cancer. Proc Natl Acad Sci U S A. 1994;91:11045–9.PubMedCentralPubMedCrossRefGoogle Scholar
  83. Pritchard EM, Stewart E, Zhu F, et al. Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor R406 after ocular delivery for retinoblastoma. Pharm Res. 2014;31:3060–72.PubMedCentralPubMedCrossRefGoogle Scholar
  84. Qin XQ, Chittenden T, Livingston DM, et al. Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev. 1992;6:953–64.PubMedCrossRefGoogle Scholar
  85. Reis AH, Vargas FR, Lemos B. More epigenetic hits than meets the eye: microRNAs and genes associated with the tumorigenesis of retinoblastoma. Front Genet. 2012;3:284. doi: 10.3389/fgene.2012.00284.PubMedCentralPubMedGoogle Scholar
  86. Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology. 1988;95:1583–7.PubMedCrossRefGoogle Scholar
  87. Robertson KD, Ait-Si-Ali S, Yokochi T, et al. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet. 2000;25:338–42.PubMedCrossRefGoogle Scholar
  88. Shackney SE, Shankey TV. Cell cycle models for molecular biology and molecular oncology: exploring new dimensions. Cytometry. 1999;35:97–116.PubMedCrossRefGoogle Scholar
  89. Sherr CJ. Cancer cell cycles. Science. 1996;274:1672–7.PubMedCrossRefGoogle Scholar
  90. Singh SK, Das D, Bhattacharjee H, et al. A rare case of adult onset retinoblastoma. Oman J Ophthalmol. 2011;4:25–7.PubMedCentralPubMedCrossRefGoogle Scholar
  91. Sparkes RS, Sparkes MC, Wilson MG, et al. Regional assignment of genes for human esterase D and retinoblastoma to chromosome band 13q14. Science. 1980;208:1042–4.PubMedCrossRefGoogle Scholar
  92. Stein GH, Beeson M, Gordon L. Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science. 1990;249:666–9.PubMedCrossRefGoogle Scholar
  93. van Harn T, Foijer F, van Vugt M, et al. Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev. 2010;24:1377–88.PubMedCentralPubMedCrossRefGoogle Scholar
  94. van Maerken T, Rihani A, van Goethem A, De Paepe A, Speleman F, Vandesompele J. Pharmacologic activation of wild-type p53 by nutlin therapy in childhood cancer. Cancer Lett. 2014;344(2):157–65.PubMedCrossRefGoogle Scholar
  95. Walkley CR, Shea JM, Sims NA, et al. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell. 2007;129:1081–95.PubMedCentralPubMedCrossRefGoogle Scholar
  96. Weintraub SJ, Chow KN, Luo RX, et al. Mechanism of active transcriptional repression by the retinoblastoma protein. Nature. 1995;375:812–5.PubMedCrossRefGoogle Scholar
  97. Welch PJ, Wang JY. A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle. Cell. 1993;75:779–90.PubMedCrossRefGoogle Scholar
  98. Whyte P, Buchkovich KJ, Horowitz JM, et al. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature. 1988;334:124–9.PubMedCrossRefGoogle Scholar
  99. Wiggs J, Nordenskjold M, Yandell D, et al. Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med. 1988;318:151–7.PubMedCrossRefGoogle Scholar
  100. Wolfel T, Hauer M, Schneider J, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science. 1995;269:1281–4.PubMedCrossRefGoogle Scholar
  101. Wong FL, Boice JJ, Abramson DH, et al. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA. 1997;278:1262–7.PubMedCrossRefGoogle Scholar
  102. Woo KI, Harbour JW. Review of 676 second primary tumors in patients with retinoblastoma: association between age at onset and tumor type. Arch Ophthalmol. 2010;128:865–70.PubMedCrossRefGoogle Scholar
  103. Xiao ZX, Chen J, Levine AJ, et al. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature. 1995;375:694–8.PubMedCrossRefGoogle Scholar
  104. Xu HJ, Xu K, Zhou Y, et al. Enhanced tumor cell growth suppression by an N-terminal truncated retinoblastoma protein. Proc Natl Acad Sci U S A. 1994;91:9837–41.PubMedCentralPubMedCrossRefGoogle Scholar
  105. Xu XL, Fang Y, Lee TC, et al. Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell. 2009;137:1018–31.PubMedCrossRefGoogle Scholar
  106. Zhang HS, Postigo AA, Dean DC. Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4a, TGFß, and contact inhibition. Cell. 1999;97:53–61.PubMedCrossRefGoogle Scholar
  107. Zhang J, Benavente CA, McEvoy J, et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 2012;481:329–34.PubMedCentralPubMedGoogle Scholar
  108. Zhu X, Dunn JM, Goddard AD, et al. Mechanisms of loss of heterozygosity in retinoblastoma. Cytogenet Cell Genet. 1992;59:248–52.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Ocular Oncology ServiceBascom Palmer Eye InstituteMiamiUSA
  2. 2.Sylvester Comprehensive Cancer CenterMiller School of Medicine, University of MiamiMiamiUSA

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