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Volume 10Nov 2009

Scientific Report

  • EMBO reports (2009) 10, 866 - 872
  • doi:10.1038/embor.2009.93

Published online: 26 June 2009

REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A–DDB1 ubiquitin ligase

Samiksha Katiyar1, Enbo Liu1, Christine A Knutzen1, Elizabeth S Lang1, Christian R Lombardo2, Sabita Sankar2, Julia I Toth1, Matthew D Petroski1, Ze'ev Ronai1 & Gary G Chiang1

  1. Signal Transduction Program, Burnham Institute for Medical Research, 10901 North Torrey, Pines Road, La Jolla, California 92037, USA
  2. Celgene, 4550 Towne Center Court, San Diego, California 92121, USA

Correspondence to:

Gary G Chiang, Tel: +1 858 795 5235; Fax: +1 858 713 6274;
E-mail: gchiang@burnham.org

Received 14 October 2008; Revised 3 April 2009; Accepted 7 April 2009

The cellular response to hypoxia involves several signalling pathways that mediate adaptation and survival. REDD1 (regulated in development and DNA damage responses 1), a hypoxia-inducible factor-1 target gene, has a crucial role in inhibiting mammalian target of rapamycin complex 1 (mTORC1) signalling during hypoxic stress. However, little is known about the signalling pathways and post-translational modifications that regulate REDD1 function. Here, we show that REDD1 is subject to ubiquitin-mediated degradation mediated by the CUL4A–DDB1–ROC1–beta-TRCP E3 ligase complex and through the activity of glycogen synthase kinase 3beta. Furthermore, REDD1 degradation is crucially required for the restoration of mTOR signalling as cells recover from hypoxic stress. Our findings define a mechanism underlying REDD1 degradation and its importance for regulating mTOR signalling.

  • Keywords:

    • REDD1,
    • mTOR,
    • hypoxia,
    • ubiquitin,
    • CUL4A