1. Biochemistry and Chemical Biology
  2. Cell Biology
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Cyclin D activates the Rb tumor suppressor by mono-phosphorylation

  1. Anil M Narasimha
  2. Manuel Kaulich
  3. Gary S Shapiro
  4. Yoon J Choi
  5. Piotr Sicinski
  6. Steven F Dowdy  Is a corresponding author
  1. University of California, San Diego School of Medicine, United States
  2. Sanofi Oncology, United States
  3. Harvard Medical School, United States
Research Article
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Cite this article as: eLife 2014;3:e02872 doi: 10.7554/eLife.02872

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

  1. Anil M Narasimha

    University of California, San Diego School of Medicine, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Manuel Kaulich

    University of California, San Diego School of Medicine, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gary S Shapiro

    Sanofi Oncology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yoon J Choi

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Piotr Sicinski

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Steven F Dowdy

    University of California, San Diego School of Medicine, La Jolla, United States
    For correspondence
    sdowdy@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Roger Davis, University of Massachusetts Medical School, United States

Publication history

  1. Received: March 23, 2014
  2. Accepted: May 22, 2014
  3. Accepted Manuscript published: May 29, 2014 (version 1)
  4. 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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