Regulation of the retinoblastoma tumor suppressor protein by cyclin/cdks.
The retinoblastoma tumor suppressor protein (pRB) is a paradigm for understanding cell cycle- and proliferation-dependent transcription and how deregulation of this process contributes to the neoplastic process in humans. The ability of pRB to regulate transcription, and consequently cell proliferation and differentiation, is regulated by the activity of cyclin/cdks. In general, phosphorylation of pRB by cyclin/cdks inactivates pRB-mediated transcriptional inhibition and growth suppression. However, it is apparent that pRB is a multi-functional protein that can inhibit transcription through various mechanisms. This review focuses on recent data to suggest that different pRB functions are progressively and cooperatively inactivated by multiple cyclin/cdk complexes during G1- and S-phase. The implications of such a model for pRB-mediated tumor suppression are discussed.
Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA. pd_adams@fccc.edu
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D000818:Animals; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000494:pharmacology; D016213:Cyclins / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000494:pharmacology; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D050720:Retinoblastoma-Like Protein p107
D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases