Journal
ELIFE
Volume 3, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.02872
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [T32 CA009523, CA108420, R01 CA083688, TG CA009523, CA169849] Funding Source: Medline
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The widely accepted model of G(1) cell cycle progression proposes that cyclin D: Cdk4/6 inactivates the Rb tumor suppressor during early G(1) phase by progressive multi-phosphorylation, termed hypo-phosphorylation, to release E2F transcription factors. However, this model remains unproven biochemically and the biologically active form(s) of Rb remains unknown. Here we find that Rb is exclusively mono-phosphorylated in early G(1) phase by cyclin D:Cdk4/6. Mono-phosphorylated Rb is composed of 14 independent isoforms that are all targeted by the E1a oncoprotein, but show preferential E2F binding patterns. At the late G(1) Restriction Point, cyclin E: Cdk2 inactivates Rb by quantum hyper-phosphorylation. Cells undergoing a DNA damage response activate cyclin D: Cdk4/6 to generate mono-phosphorylated Rb that regulates global transcription, whereas cells undergoing differentiation utilize un-phosphorylated Rb. These observations fundamentally change our understanding of G(1) cell cycle progression and show that mono-phosphorylated Rb, generated by cyclin D:Cdk4/6, is the only Rb isoform in early G(1) phase.
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