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An intact NEDD8 pathway is required for Cullin‐dependent ubiquitylation in mammalian cells

Michael Ohh, William Y Kim, Javid J Moslehi, Yuzhi Chen, Vincent Chau, Margaret A Read, William G Kaelin

Author Affiliations

  1. Michael Ohh1,
  2. William Y Kim1,
  3. Javid J Moslehi1,
  4. Yuzhi Chen2,
  5. Vincent Chau3,
  6. Margaret A Read4 and
  7. William G Kaelin Jr*,1,5
  1. 1 Department of Adult Oncology, Dana‐Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
  2. 2 Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA
  3. 3 Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
  4. 4 Millenium Pharmaceuticals, Cambridge, MA, 02139, USA
  5. 5 Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
  1. *Corresponding author. Tel: +1 617 632 3975; Fax: +1 617 632 4760; E-mail: william_kaelin{at}dfci.harvard.edu
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Abstract

Skp1‐Cdc53/Cul1‐F‐box (SCF) complexes constitute a class of E3 ubiquitin ligases. Recently, a multiprotein complex containing pVHL, elongin C and Cul2 (VEC) was shown to structurally and functionally resemble SCF complexes. Cdc53 and the Cullins can become covalently linked to the ubiquitin‐like molecule Rub1/NEDD8. Inhibition of neddylation inhibits SCF function in vitro and in yeast and plants. Here we show that ongoing neddylation is likewise required for VEC function in vitro and for the degradation of SCF and VEC targets in mammalian cells. Thus, neddylation regulates the activity of two specific subclasses of mammalian ubiquitin ligases.

  • Received June 6, 2001.
  • Revision received December 5, 2001.
  • Accepted December 13, 2001.
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