Skip to main content
Log in

Retinoblastoma protein: a central processing unit

  • Review
  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

The retinoblastoma protein (pRb) is one of the key cell-cycle regulating proteins and its inactivation leads to neoplastic transformation and carcinogenesis. This protein regulates critical G1-to-S phase transition through interaction with the E2F family of cell-cycle transcription factors repressing transcription of genes required for this cell-cycle check-point transition. Its activity is regulated through network sensing intracellular and extracellular signals which block or permit phosphorylation (inactivation) of the Rb protein. Mechanisms of Rb-dependent cell-cycle control have been widely studied over the past couple of decades. However, recently it was found that pRb also regulates apoptosis through the same interaction with E2F transcription factors and that Rb-E2F complexes play a role in regulating the transcription of genes involved in differentiation and development.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

Cdk:

cyclin-dependent kinase

HDAC:

histone deacetylase

INK4:

inhibitor of kinase 4

pRb:

retinoblastoma protein

TNF:

tumour necrosis factor

References

  • Adnane J, Shao Z and Robbins P D 1995 The retinoblastoma susceptibility gene product represses transcription when directly bound to the promoter; J. Biol. Chem. 270 8837–8843

    Article  PubMed  CAS  Google Scholar 

  • Ait-Si-Ali S, Guasconi V, Fritsch L, Yahi H, Sekhri R, Naguibneva I, Robin P, Cabon F, Polesskaya A and Harel-Bellan A 2004 A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells; EMBO J. 23 605–615

    Article  PubMed  CAS  Google Scholar 

  • Borges H L, Hunton I C and Wang J Y J 2007 Reduction of apoptosis in Rb-deficient embryos via Abl knockout; Oncogene 26 3868–3877

    Article  PubMed  CAS  Google Scholar 

  • Brehm A, Miska E A, McCance D J, Reid J L, Bannister A J and Kouzarides T 1998 Retinoblastoma protein recruits histone deacetylase to repress transcription; Nature (London) 391 597–601

    Article  CAS  Google Scholar 

  • Carreira S, Goodal J, Aksan I, La Rocca S A, Galibert M D, Denat L, Larue L and Goding C R 2005 Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression; Nature (London) 433 764–769

    Article  CAS  Google Scholar 

  • Cavanaugh A H, Hempel W M, Taylor L J, Rogalsky V, Todorov G and Rothblum L I 1995 Activity of RNA polymerase I transcription factor UBF blocked by RB gene product; Nature (London) 374 177–180

    Article  CAS  Google Scholar 

  • Chau B N, Borges H B, Chen T-T, Masselli A, Hunton I C and Wang J Y 2002 Signal-dependent protection from apoptosis in mice expressing caspase-resistant Rb; Nat. Cell Biol. 4 757–765

    Article  PubMed  CAS  Google Scholar 

  • Chau B N and Wang J Y 2003 Coordinated regulation of life and death by Rb; Nat. Rev. Cancer 3 130–138

    Article  PubMed  CAS  Google Scholar 

  • Clarke A R, Maandag E R, van Roon M, van der Lugt N M, van der Valk M, Hooper M L, Berns A and Riele H 1992 Requirement for a functional Rb-1 gene in murine development; Nature (London) 359 328–330

    Article  CAS  Google Scholar 

  • Deléhouzée S, Yoshikawa T, Sawa C, Sawada J, Ito T, Omori M, Wada T, Yamaguchi Y, Kabe Y and Handa H 2005 GABP, HCF-1 and YY1 are involved in Rb gene expression during myogenesis; Genes to Cells 10 717–731

    Article  PubMed  Google Scholar 

  • Dirlam A, Spike B T and MacLeod K F 2007 Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts; Mol. Cell. Biol. 27 8713–8728

    Article  PubMed  CAS  Google Scholar 

  • Du W and Pogoriler J 2006 Retinoblastoma family genes; Oncogene 25 5190–5200

    Article  PubMed  CAS  Google Scholar 

  • Dyson N, Howley P M, Munger K and Harlow E 1989 The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product; Science 243 934–937

    Article  PubMed  CAS  Google Scholar 

  • Ezhevsky S A, Nagahara H, Vocero-Akbani A M, Gius D R, Wei M C and Dowdy S F 1997 Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb; Proc. Natl. Acad. Sci. USA 94 10699–10704

    Article  PubMed  CAS  Google Scholar 

  • Fattman C L, Delach S M, Dou Q P and Johnson D E 2001 Sequential two-step cleavage of the retinoblastoma protein by caspase-3/-7 during etoposide induced apoptosis; Oncogene 20 2918–2926

    Article  PubMed  CAS  Google Scholar 

  • Felsani A, Mileo A M and Paggi M G 2006 Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins; Oncogene 25 5277–5285

    Article  PubMed  CAS  Google Scholar 

  • Felsenfeld G 1992 Chromatin as a essential part of transcriptional mechanism; Nature (London) 355 219–224

    Article  CAS  Google Scholar 

  • Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A and Trouche D 1998 The three members of the pocket family share the ability to repress E2F activity through recruitment of a histone deacetylase; Proc. Natl. Acad. Sci. USA 95 10493–10498

    Article  PubMed  CAS  Google Scholar 

  • Garnovskaya M N, Mukhin Y V, Vlasova T M, Grewal J S, Ullian M E, Tholanikunnel B G and Raymond J R 2004 Mitogen-induced rapid phosphorylation of serine 795 of the retinoblastoma gene product in vascular smooth muscle cells involves ERK activation; J. Biol. Chem. 279 24899–24905

    Article  PubMed  CAS  Google Scholar 

  • Giacinti C and Giordano A 2006 RB and cell cycle progression; Oncogene 25 5220–5227

    Article  PubMed  CAS  Google Scholar 

  • Goodrich D W, Wang N P, Qian Y-W, Lee E Y -H P and Lee W-H 1991 The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle; Cell 67 293–302

    Article  PubMed  CAS  Google Scholar 

  • Grunstein M 1997 Histone acetylation in chromatin structure and transcription; Nature (London) 389 349–352

    Article  CAS  Google Scholar 

  • Guo Z, Yikang S, Yoshida H, Mak T W and Zacksenhaus E 2001 Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis; Cancer Res. 61 8395–8400

    PubMed  CAS  Google Scholar 

  • Hamel P A, Gill R M, Phillips R A and Gallie B L 1992 Transcriptional repression of the E2-containing promoters EIIaE, c-myc, and RB1 by the product of the RB1 gene; Mol. Cell. Biol. 12 3431–3438

    PubMed  CAS  Google Scholar 

  • Harbour J W, Luo R X, Dei Santi A, Postigo A A and Dean D C 1999 Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb function as a cell move through G1; Cell 98 856–869

    Article  Google Scholar 

  • Hasig C A, Fleischer T C, Billin A N, Schreiber S L and Ayer D E 1997 Histone deacetylase activity is required for full transcriptional repression by mSin3A; Cell 89 341–347

    Article  Google Scholar 

  • He S, Cook B L, Deverman B E, Weihe U, Zhang F, Prachand V, Zheng J and Weintraub S J 2000 E2F is required to prevent inappropriate S-phase entry of mammalian cellsM; Mol. Cell. Biol. 20 363–371

    Article  PubMed  CAS  Google Scholar 

  • Helin K, Harlow E and Fattaey A 1993 Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein; Mol. Cell. Biol. 13 6501–6508

    PubMed  CAS  Google Scholar 

  • Helt A-M and Galloway D A 2003 Mechanisms by which tumor virus oncoproteins target the Rb family of pocket proteins; Carcinogenesis 24 159–169

    Article  PubMed  CAS  Google Scholar 

  • Hiebert S W, Chellapan S P, Horowitz J M and Nevins J R 1992 The interaction of Rb with E2F coincides with an inhibition of the transcriptional activity of E2F; Genes Dev. 6 177–185

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hirai H, Roussel M F, Kato J Y, Ashmun R A and Sherr C J 1995 Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6; Mol. Cell. Biol. 15 2672–2681

    PubMed  CAS  Google Scholar 

  • Horowitz J M, Park S H, Bogenmann E, Cheng J C, Yandell D W, Kaye F J, Minna J D, Dryja T P and Weinberg R A 1990 Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells; Proc. Natl. Acad. Sci. USA 87 2775–2779

    Article  PubMed  CAS  Google Scholar 

  • Iavarone A, King E R, Dai X M, Leone G, Stanley E R and Lasorella A 2004 Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages; Nature (London) 432 1040–1045

    Article  CAS  Google Scholar 

  • Khatib Z A, Matsushime H, Valentine M, Shapiro D N, Sherr C J and Look A T 1993 Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas; Cancer Res. 53 5535–5541

    PubMed  CAS  Google Scholar 

  • Knudsen E S and Wang J Y J 1996 Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites; J. Biol. Chem. 261 8313–8320

    Google Scholar 

  • Lin B T and Wang J Y 1992 Cell cycle regulation of retinoblastoma protein phosphorylation; Ciba Found. Symp. 170 227–241

    PubMed  CAS  Google Scholar 

  • Liu X, Clements A, Zhao K and Marmorstein R 2006 Structure of the human papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor; J. Biol. Chem. 281 578–586

    Article  PubMed  CAS  Google Scholar 

  • Liu X and Marmorstein R 2007 Structure of the retinoblastoma protein bound to adenovirus E1A reveals the molecular basis for viral oncoprotein inactivation of a tumor suppressor; Genes Dev. 21 2711–2716

    Article  PubMed  CAS  Google Scholar 

  • Lukas J, Muller H, Bartkova J, Spitkovsky D, Kjerulff A A, Jansen-Durr P, Strauss M and Bartek J 1994 DNA Tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell’s requirement for cyclin D1 function in G1; J. Cell Biol. 125 625–638

    Article  PubMed  CAS  Google Scholar 

  • Ludlow J W, DeCaprio J A, Huang C-M, Lee W-H, Paucha E and Livingston D M 1989 SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family; Cell 56 57–65

    Article  PubMed  CAS  Google Scholar 

  • Lundberg A S and Weinberg R A 1998 Functional inactivation of the retinoblastoma protein requires sequential modification of retinoblastoma protein by at least two distinct cyclin-Cdk complexes; Mol. Cell. Biol. 18 735–761

    Google Scholar 

  • Luo R X, Postigo A A and Dean D C 1998 Rb interacts with histone deacetylase to repress transcription; Cell 92 463–473

    Article  PubMed  CAS  Google Scholar 

  • Macleod K F, Hu Y and Jacks T 1996 Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system; EMBO J. 15 6178–6188

    PubMed  CAS  Google Scholar 

  • Masselli A and Wang J Y J 2006 Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli; Oncogene 25 1290–1298

    Article  PubMed  CAS  Google Scholar 

  • Miskolczi P, Lendvai A, Horváth G V, Pettkó-Szandtner A, Dudits D 2007 Conserved functions of retinoblastoma proteins: from purple retina to green plant cells; Plant Sci. 172 671–683

    Article  CAS  Google Scholar 

  • Mittnacht S and Bosshof C 2000 Vital cyclins; Rev. Med. Virol. 10 175–184

    Article  PubMed  CAS  Google Scholar 

  • Morisaki H, Fujimoto A, Ando A, Nagata Y, Ikeda K and Nakanishi M 1997 Cell cycle-dependent phosphorylation of p27 cyclindependent kinase (Cdk) inhibitor by cyclin E/Cdk2; Biochem. Biophys. Res. Commun. 240 386–390

    Article  PubMed  CAS  Google Scholar 

  • Moreland J L, Gramada A, Buzko O V, Zhang Q and Bourne P E 2005 The molecular biology toolkit (MBT): a modular platform for developing molecular visualization applications; BMC Bioinformatics 6 21

    Article  PubMed  Google Scholar 

  • Nguyen D X, Baglia L A, Huang S-M, Baker C M and McCance D J 2004 Acetylation regulates the differentiation-specific functions of the retinoblastoma protein; EMBO J. 23 1609–1618

    Article  PubMed  CAS  Google Scholar 

  • Parra M A and Wyrick J J 2007 Regulation of gene transcription by the histone H2A N-terminal domain; Mol. Cell. Biol. 27 7641–7648

    Article  PubMed  CAS  Google Scholar 

  • Pazin M J and Kadonaga J T 1997 What’s up and down with histone deacetylation and transcription?; Cell 89 325–328

    Article  PubMed  CAS  Google Scholar 

  • Perez-Roger I, Solomon D L, Sewing A and Land H 1997 Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27 (Kip1) binding to newly formed complexes; Oncogene 14 2373–2381

    Article  PubMed  CAS  Google Scholar 

  • Qian Y W, Wang Y C, Hollingsworth R E Jr, Jones D, Ling N and Lee E Y 1993 A retinoblastoma-binding protein related to a negative regulator of Ras in yeast; Nature (London) 364 648–652

    Article  CAS  Google Scholar 

  • Reissmann P T, Koga H, Figlin R A, Holmes E C and Slamon D J 1999 Amplification and overexpression of the cyclin D1 and epidermal growth factor receptor genes in non-small-cell lung cancer; J. Cancer Res. Clin. Oncol. 125 61–70

    Article  PubMed  CAS  Google Scholar 

  • Rekhtman N, Choe K S, Matushansky I, Murray S, Stopka T and Skoultchi A I 2003 PU.1 and pRb interact and cooperate to repress GATA-1 and block erythroid differentiation; Mol. Cell. Biol. 23 7460–7474

    Article  PubMed  CAS  Google Scholar 

  • Rubin E, Mittnach S, Villa-Moruzzi E and Ludlow J W 2001 Site-specific and temporally regulated retinoblastoma protein dephosphorylation by protein phosphatase type I; Oncogene 20 3776–3785

    Article  PubMed  CAS  Google Scholar 

  • Sage C, Huang M, Karimi K, Gutierrez G, Vollrath M A, Zhang D S, Garcia Anoveros J, Hinds P W, Corvin J T, Corey D P and Chen Z-Y 2005 Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein; Science 307 1114–1118

    Article  PubMed  CAS  Google Scholar 

  • Sankaran V G, Orkin S H and Walkley C R 2008 Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis; Genes Dev. 22 463–475

    Article  PubMed  CAS  Google Scholar 

  • Sellers W R, Rodgers J W and Kaelin W Jr 1995 A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites; Proc. Natl. Acad. Sci. USA 92 11544–11548

    Article  PubMed  CAS  Google Scholar 

  • Shapiro G I, Park J E, Edwards C D, Mao L, Merlo A, Sidransky D, Ewen M E and Rollins B J 1995 Multiple mechanisms of p16INK4a in non-small cell lung cancer cell lines; Cancer Res. 55 6200–6209

    PubMed  CAS  Google Scholar 

  • Sherr C J 1996 Cancer cell cycles; Science 274 1672–1677

    Article  PubMed  CAS  Google Scholar 

  • Sherr C J and McCormic F 2002 The RB and p53 pathways in cancer; Cancer Cell 2 103–112

    Article  PubMed  CAS  Google Scholar 

  • Siddiqui H, Solomon D A, Gunawardena R W, Wang Y and Knudsen E S 2003 Histone deacetylation of RB-responsive promoters: requisite for specific gene repression but dispensable for cell cycle inhibition; Mol. Cell. Biol. 23 7719–7731

    Article  PubMed  CAS  Google Scholar 

  • Siddiqui H, Fox S R, Gunawardena R W, Knudsen E S 2007 Loss of RB compromises specific heterochromatin modifications and modulates HP1alpha dynamics; J. Cell. Physiol. 211 131–137

    Article  PubMed  CAS  Google Scholar 

  • Simpson M T W, MacLaurin J G, Xu D, Ferguson K L, Vanderluit J L, Davoli M A, Roy S, Nicholson D W, Robertson G S, Park D S and Slack R S 2001 Caspase 3 deficiency rescues peripheral nervous system defect in retinoblastoma nullizygous mice; J. Neurosci. 21 7089–7098

    PubMed  CAS  Google Scholar 

  • Tan X, Martin S J, Green D R and Wang J Y 1997 Degradation of retinoblastoma protein in tumor necrosis factor- and CD95-induced cell death; J. Biol. Chem. 272 9613–9616

    Article  PubMed  CAS  Google Scholar 

  • Taunton J, Hassig C A and Schreiber S L A 1996 Mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p; Science 272 408–411

    Article  PubMed  CAS  Google Scholar 

  • Tsai K, Hu Y, Macleod K, 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

    Article  PubMed  CAS  Google Scholar 

  • Xiao B, Spencer J, Clements A, Ali-Khan N, Mittnacht S, Broceño C, Burghammer M, Perrakis A, Marmorstein R and Gamblin S J 2003 Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation; Proc. Natl. Acad. Sci. USA 100 2363–2368

    Article  PubMed  CAS  Google Scholar 

  • Xing E P, Yang G-Y, Wang L-D, Shi S T and Yang C S 1999 Loss of heterozygosity of the Rb gene correlates with pRb protein expression and associates with p53 alteration in human esophageal cancer; Clin. Cancer Res. 5 1231–1240

    PubMed  CAS  Google Scholar 

  • Weinberg R A 1995 The retinoblastoma protein and cell cycle control; Cell 81 323–330

    Article  PubMed  CAS  Google Scholar 

  • Weintraub S J, Prater C A and Dean D C 1992 Retinoblastoma protein switches the E2F site from positive to negative element; Nature (London) 358 259–261

    Article  CAS  Google Scholar 

  • Weintraub S J, Chow K N B, Luo R X, Zhang S H, He S and Dean D C 1995 Mechanism of active transcriptional repression by the retinoblastoma protein; Nature (London) 375 812–815

    Article  CAS  Google Scholar 

  • White R J, Trouche J, Martin K, Jackson S P and Kouzarides T 1996 Repression of RNA polymerase III transcription by the retinoblastoma protein; Nature (London) 382 88–90

    Article  CAS  Google Scholar 

  • Whyte P, Bukowich K J, Horowitz J M, Friend S H, Raybuck M, Weinberg R A and Harlow E 1988 Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product; Nature (London) 334 124–129

    Article  CAS  Google Scholar 

  • Wolffe A P and Pruss D 1996 Targeting chromatin disruption: transcription regulators that acetylase histones; Cell 84 817–819

    Article  PubMed  CAS  Google Scholar 

  • Wong S and Weber J D 2007 Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1; Biochem. J. 407 451–460

    Article  PubMed  CAS  Google Scholar 

  • Zarkowska T and Mittnacht S 1997 Differential phosphorylation of the retinoblastoma protein by G1/S cyclin-dependent kinases; J. Biol. Chem. 272 12738–12746

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zhang H S, Postigo A A and Dean D C 1999 Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4a, TGFβ and contact inhibition; Cell 97 53–61

    Article  PubMed  CAS  Google Scholar 

  • Zhu J W, DeRyckere D, Li F X, Wan Y Y and DeGregori J 1999 A role of E2F-1 in the induction of ARF, p53 and apoptosis during thymic negative selection; Cell Growth Differ. 10 829–838

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Poznic.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Poznic, M. Retinoblastoma protein: a central processing unit. J Biosci 34, 305–312 (2009). https://doi.org/10.1007/s12038-009-0034-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12038-009-0034-2

Keywords

Navigation