title: Regulation of the retinoblastoma-E2F pathway by the ubiquitin-proteasome system.
abstract: The retinoblastoma tumor suppressor (RB) and its related family members p107 and p130 regulate cell proliferation through the transcriptional repression of genes involved in cellular G1 to S phase transition. However, RB proteins are functionally versatile, and numerous genetic and biochemical studies point to expansive roles in cellular growth control, pluripotency, and apoptotic response. For the vast majority of genes, RB family members target the E2F family of transcriptional activators as an integral component of its gene regulatory mechanism. These interactions are regulated via reversible phosphorylation by Cyclin/Cyclin-dependent kinase (Cdk) complexes, a major molecular mechanism that regulates transcriptional output of RB/E2F target genes. Recent studies indicate an additional level of regulation involving the ubiquitin-proteasome system that renders pervasive control over each component of the RB pathway. Disruption of the genetic circuitry for proteasome-mediated targeting of the RB pathway has serious consequences on development and cellular transformation, and is associated with several forms of human cancer. In this review, we discuss the role of the ubiquitin-proteasome system in proteolytic control of RB-E2F pathway components, and recent data that points to surprising non-proteolytic roles for the ubiquitin-proteasome system in novel transcriptional regulatory mechanisms.
authors: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
authors: Satyaki
authors: S
authors: Sengupta
authors: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: henryrw@msu.edu.
authors: R William
authors: RW
authors: Henry
mesh_terms: D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D050684:E2F Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000235:genetics*
chemical_list: C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D025801:Ubiquitin; D018844:Cyclin-Dependent Kinases; D046988:Proteasome Endopeptidase Complex
keywords: E2F; Proteasome; RB; Retinoblastoma; Transcription regulation; Ubiquitin; p107; p130