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

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

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, United States.
2
Department of Genetics, Harvard Medical School, Boston, United States.

Abstract

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.

KEYWORDS:

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

PMID:
24876129
PMCID:
PMC4076869
DOI:
10.7554/eLife.02872
[Indexed for MEDLINE]
Free PMC Article

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