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Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK.

The transcriptional coactivator PPAR gamma coactivator 1 alpha (PGC-1alpha) is a key regulator of metabolic processes such as mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver. Reduced levels of PGC-1alpha in humans have been associated with type II diabetes. PGC-1alpha contains a negative regulatory domain that attenuates its transcriptional activity. This negative regulation is removed by phosphorylation of PGC-1alpha by p38 MAPK, an important kinase downstream of cytokine signaling in muscle and beta-adrenergic signaling in brown fat. We describe here the identification of p160 myb binding protein (p160MBP) as a repressor of PGC-1alpha. The binding and repression of PGC-1alpha by p160MBP is disrupted by p38 MAPK phosphorylation of PGC-1alpha. Adenoviral expression of p160MBP in myoblasts strongly reduces PGC-1alpha's ability to stimulate mitochondrial respiration and the expression of the genes of the electron transport system. This repression does not require removal of PGC-1alpha from chromatin, suggesting that p160MBP is or recruits a direct transcriptional suppressor. Overall, these data indicate that p160MBP is a powerful negative regulator of PGC-1alpha function and provide a molecular mechanism for the activation of PGC-1alpha by p38 MAPK. The discovery of p160MBP as a PGC-1alpha regulator has important implications for the understanding of energy balance and diabetes.

Pubmed ID: 14744933

Authors

  • Fan M
  • Rhee J
  • St-Pierre J
  • Handschin C
  • Puigserver P
  • Lin J
  • J√§eger S
  • Erdjument-Bromage H
  • Tempst P
  • Spiegelman BM

Journal

Genes & development

Publication Data

February 1, 2004

Associated Grants

  • Agency: NEI NIH HHS, Id: 5T32EY07110
  • Agency: NIDDK NIH HHS, Id: DK54477
  • Agency: NCI NIH HHS, Id: P30 CA08748

Mesh Terms

  • Animals
  • Carrier Proteins
  • Cell Respiration
  • Cells, Cultured
  • Energy Metabolism
  • Gene Expression Regulation
  • MAP Kinase Signaling System
  • Mitochondria, Muscle
  • Mitogen-Activated Protein Kinases
  • Muscle, Skeletal
  • Nuclear Proteins
  • Nucleocytoplasmic Transport Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • p38 Mitogen-Activated Protein Kinases