G1 cyclin/CDK-independent phosphorylation and accumulation of p130 during the transition from G1 to G0 lead to its association with E2F-4.
During the transition from G1 to G0, p130 undergoes a specific phosphorylation event-leading to p130-form 2- that is mediated by a kinase/s other than the known G1, S and G2/M cyclin/CDKs. Changes in the phosphorylation status of p130 during this transition are responsible, at least in part, for the concomitant formation of p130/E2F-4 complexes, which are characteristic of G0. These complexes remain abundant during early G1 upon restimulation, but not after mitosis, and are dissociated in mid G1 when p130 is abruptly hyperphosphorylated to form 3. Subsequently, p130 forms 1 and 2 are no longer detected during the remainder of the cell cycle. Consistently, phosphorylation to form 3 and dissociation from E2F-4 complexes is reproduced by a cyclin/CDK holoenzyme in vitro. TGF-beta-induced G1 arrest abrogates cyclin/CDK phosphorylation of p130 but not phosphorylation to form 2. The cell cycle-dependent phosphorylation pattern of p130 is thus shown to comprise two distinct steps that are catalyzed by different kinases. The differential regulation of p130 and pRB phosphorylation during the transition from G1 to G0 may explain the fact that p130 and E2F-4 are the major components of E2F complexes in quiescent cells. Moreover, the newly described phosphorylation of p130 at the transition from G1 to G0 defines a novel mechanism of cell cycle exit regulation.
Mayol
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Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Garriga
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Graña
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D016475:3T3 Cells / Q000378:metabolism*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050704:E2F4 Transcription Factor; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins; D016192:Resting Phase, Cell Cycle / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D016213:Cyclins; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D010750:Phosphoproteins; D011506:Proteins; C493837:RBL2 protein, human; C493838:Rbl2 protein, mouse; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D018844:Cyclin-Dependent Kinases