Journal
GENES & DEVELOPMENT
Volume 22, Issue 2, Pages 252-264Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1624208
Keywords
Cdc4; Fbw7; PGC-1; protein degradation; ubiquitin-mediated proteolysis; oxidative stress
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Funding
- NCI NIH HHS [R01 CA078343, CA 78343, R56 CA078343] Funding Source: Medline
- NIDDK NIH HHS [R01 DK064951, DK 64951] Funding Source: Medline
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Peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator-1 alpha (PGC-1 alpha) is a highly regulated transcriptional coactivator that coordinates energy metabolism in mammals. Misregulation of PGC-1 alpha has been implicated in the pathogenesis of several human diseases, including diabetes, obesity, and neurological disorders. We identified SCFCdc4 as an E3 ubiquitin ligase that regulates PGC-1 alpha through ubiquitin-mediated proteolysis. PGC-1 alpha contains two Cdc4 phosphodegrons that bind Cdc4 when phosphorylated by Glycogen Synthase Kinase 3 beta ( GSK3 beta) and p38 MAPK, leading to SCFCdc4-dependent ubiquitylation and proteasomal degradation of PGC-1 alpha. Furthermore, SCFCdc4 negatively regulates PGC-1 alpha-dependent transcription. We demonstrate that RNAi-mediated reduction of Cdc4 in primary neurons results in an increase of endogenous PGC-1 alpha protein, while ectopic expression of Cdc4 leads to a reduction of endogenous PGC-1 alpha protein. Finally, under conditions of oxidative stress in neurons, Cdc4 levels are decreased, leading to an increase in PGC-1 alpha protein and PGC-1 alpha-dependent transcription. These results suggest that attenuation of SCFCdc4-dependent proteasomal degradation of PGC-1 alpha has a role in mediating the PGC-1 alpha-dependent transcriptional response to oxidative stress.
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