Cyclin D activates the Rb tumor suppressor by mono-phosphorylation
- University of California, San Diego School of Medicine, United States
- Sanofi Oncology, United States
- Harvard Medical School, 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. Here 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.
Article and author information
Author details
Reviewing Editor
- Roger Davis, University of Massachusetts Medical School, United States
Version history
- Received: March 23, 2014
- Accepted: May 22, 2014
- Accepted Manuscript published: May 29, 2014 (version 1)
- Version of Record published: July 1, 2014 (version 2)
Copyright
© 2014, Narasimha et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cyclin D activates the Rb tumor suppressor by mono-phosphorylation
eLife 3:e02872.
https://doi.org/10.7554/eLife.02872
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