SCFCdc4 acts antagonistically to the PGC-1α transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis

Brian L. Olson, M. Benjamin Hock, Susanna Ekholm-Reed, James A. Wohlschlegel, Kumlesh K. Dev, Anastasia Kralli, Steven I. Reed

Research output: Contribution to journalArticle

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) is a highly regulated transcriptional coactivator that coordinates energy metabolism in mammals. Misregulation of PGC-1α 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-1α through ubiquitin-mediated proteolysis. PGC-1α contains two Cdc4 phosphodegrons that bind Cdc4 when phosphorylated by Glycogen Synthase Kinase 3β (GSK3β) and p38 MAPK, leading to SCFCdc4-dependent ubiquitylation and proteasomal degradation of PGC-1α. Furthermore, SCFCdc4 negatively regulates PGC-1α-dependent transcription. We demonstrate that RNAi-mediated reduction of Cdc4 in primary neurons results in an increase of endogenous PGC-1α protein, while ectopic expression of Cdc4 leads to a reduction of endogenous PGC-1α protein. Finally, under conditions of oxidative stress in neurons, Cdc4 levels are decreased, leading to an increase in PGC-1α protein and PGC-1α-dependent transcription. These results suggest that attenuation of SCFCdc4-dependent proteasomal degradation of PGC-1α has a role in mediating the PGC-1α-dependent transcriptional response to oxidative stress.

Original languageEnglish (US)
Pages (from-to)252-264
Number of pages13
JournalGenes and Development
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2008
Externally publishedYes

Fingerprint

Ubiquitin
Proteolysis
Oxidative Stress
Glycogen Synthase Kinase 3
Neurons
Peroxisome Proliferator-Activated Receptors
Proteins
Ubiquitin-Protein Ligases
Ubiquitination
p38 Mitogen-Activated Protein Kinases
RNA Interference
Nervous System Diseases
Energy Metabolism
Mammals
Obesity

Keywords

  • Cdc4
  • Fbw7
  • Oxidative stress
  • PGC-1
  • Protein degradation
  • Ubiquitin-mediated proteolysis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

SCFCdc4 acts antagonistically to the PGC-1α transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis. / Olson, Brian L.; Hock, M. Benjamin; Ekholm-Reed, Susanna; Wohlschlegel, James A.; Dev, Kumlesh K.; Kralli, Anastasia; Reed, Steven I.

In: Genes and Development, Vol. 22, No. 2, 15.01.2008, p. 252-264.

Research output: Contribution to journalArticle

Olson, Brian L. ; Hock, M. Benjamin ; Ekholm-Reed, Susanna ; Wohlschlegel, James A. ; Dev, Kumlesh K. ; Kralli, Anastasia ; Reed, Steven I. / SCFCdc4 acts antagonistically to the PGC-1α transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis. In: Genes and Development. 2008 ; Vol. 22, No. 2. pp. 252-264.
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AU - Hock, M. Benjamin

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AU - Wohlschlegel, James A.

AU - Dev, Kumlesh K.

AU - Kralli, Anastasia

AU - Reed, Steven I.

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