Modulation of pRB/E2F functions in the regulation of cell cycle and in cancer.
Cell proliferation is regulated by the cell cycle, and in order to divide the cell must enter a mitotic state. Prior to mitosis the cell is required to pass through a number of checkpoints, including the critical G1/S restriction point governed by the successive phosphorylation of the retinoblastoma protein, pRb. The various proteins and regulatory factors governing pRb phosphorylation have been a major focus of study in recent years, given the central importance of G1/S transition deregulation in cancer development. This review summarises the molecular biology around the G1/S transition, focussing on the critical roles of the transcription factor family E2F and the cyclin-dependent kinase (CDK) and cyclin families involved in E2F release from pRb. Interestingly, E2F release from pRb is associated with cell proliferation; however, above a certain threshold E2F has the potential to trigger apoptosis. The review focuses on the following topics: (i) how E2F and other substrates bind to pRb at the molecular level; (ii) mechanisms by which pRb function is modulated within the cell; (iii) mechanisms that inhibit or enhance cell proliferation via the pRb/E2F pathway; (iv) how E2F can potentiate apoptotic pathways; and (v) what controls whether E2F mediates cell proliferation or apoptosis. The case for the development of agents that perturb pRb:E2F interactions will be made, as a strategy to further inform the molecular biology around this important target and as a therapeutic strategy against cancer.
Seville
Lucy L
LL
School of Pharmacy, The Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
Shah
Nita
N
Westwell
Andrew D
AD
Chan
Weng C
WC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D014157:Transcription Factors