title: The biochemical basis of CDK phosphorylation-independent regulation of E2F1 by the retinoblastoma protein.
abstract: The pRB (retinoblastoma protein) has a central role in the control of the G(1)-S phase transition of the cell cycle that is mediated in part through the regulation of E2F transcription factors. Upon S-phase entry pRB is phosphorylated extensively, which in turn releases bound E2Fs to drive the expression of the genes required for S-phase progression. In the present study, we demonstrate that E2F1-maintains the ability to interact with ppRB (hyperphosphorylated pRB). This interaction is dependent upon the 'specific' E2F1-binding site located in the C-terminal domain of pRB. A unique region of the marked box domain of E2F1 contacts the 'specific' site to mediate the interaction with ppRB. The mechanistic basis of the interaction between E2F1 and ppRB is subtle. A single substitution between valine and proline residues in the marked box distinguishes E2F1's ability to interact with ppRB from the inability of E2F3 to bind to the 'specific' site in ppRB. The E2F1-pRB interaction at the 'specific' site also maintains the ability to regulate the transcriptional activation of E2F1 target genes. These data reveal a mechanism by which E2F1 regulation by pRB can persist, when pRB is hyperphosphorylated and presumed to be inactive.
authors.affiliation: London Regional Cancer Program, University of Western Ontario, London, Ontario, N6A 4L6, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cecchini
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase; D015533:Transcriptional Activation
chemical_list: D050687:E2F1 Transcription Factor; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases