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SCF^Cdc4 acts antagonistically to the PGC-1 transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis

¹ Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA; ² Department of Chemical Physiology and and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA; ³ Molecular and Cellular Neuroscience, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland

Peroxisome proliferator-activated receptor (PPAR) coactivator-1 (PGC-1) is a highly regulated transcriptional coactivator that coordinates energy metabolism in mammals. Misregulation of PGC-1 has been implicated in the pathogenesis of several human diseases, including diabetes, obesity, and neurological disorders. We identified SCF^Cdc4 as an E3 ubiquitin ligase that regulates PGC-1 through ubiquitin-mediated proteolysis. PGC-1 contains two Cdc4 phosphodegrons that bind Cdc4 when phosphorylated by Glycogen Synthase Kinase 3β (GSK3β) and p38 MAPK, leading to SCF^Cdc4-dependent ubiquitylation and proteasomal degradation of PGC-1. Furthermore, SCF^Cdc4 negatively regulates PGC-1-dependent transcription. We demonstrate that RNAi-mediated reduction of Cdc4 in primary neurons results in an increase of endogenous PGC-1 protein, while ectopic expression of Cdc4 leads to a reduction of endogenous PGC-1 protein. Finally, under conditions of oxidative stress in neurons, Cdc4 levels are decreased, leading to an increase in PGC-1 protein and PGC-1-dependent transcription. These results suggest that attenuation of SCF^Cdc4-dependent proteasomal degradation of PGC-1 has a role in mediating the PGC-1-dependent transcriptional response to oxidative stress.

[Keywords: Cdc4; Fbw7; PGC-1; protein degradation; ubiquitin-mediated proteolysis; oxidative stress]]

Received March 13, 2007; revised version accepted November 9, 2007.

⁵ Present addresses: Department of Biological Sciences, Saint Cloud State University, Saint Cloud, MN 56301, USA;

⁶ Department of Biological Chemistry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA;

⁷ Departments of Anatomy and Neuroscience, University College of Cork, School of Medicine, Cork, Ireland.

⁸ Corresponding authors.

E-MAIL sreed{at}scripps.edu; FAX (858) 784-2781.

⁹ E-MAIL kralli{at}scripps.edu; FAX (858) 784-9132.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1624208

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