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Elife. 2014 Jun 4;3. doi: 10.7554/eLife.02872.

Cyclin D activates the Rb tumor suppressor by mono-phosphorylation.

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Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, United States.
Department of Genetics, Harvard Medical School, Boston, United States.


The widely accepted model of G1 cell cycle progression proposes that cyclin D:Cdk4/6 inactivates the Rb tumor suppressor during early G1 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. In this study, we find that Rb is exclusively mono-phosphorylated in early G1 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 G1 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 G1 cell cycle progression and show that mono-phosphorylated Rb, generated by cyclin D:Cdk4/6, is the only Rb isoform in early G1 phase.


G1 phase; Rb tumor suppressor; biochemistry; cell biology; cell cycle; cyclin D:Cdk4; human; mono-phosphorylated Rb; p16

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