Journal
GENES & DEVELOPMENT
Volume 18, Issue 3, Pages 278-289Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1152204
Keywords
PGC-1 alpha; Mybbp1a; mitochondria; repressor; p38 MAPK
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Funding
- NCI NIH HHS [P30 CA008748, P30 CA08748] Funding Source: Medline
- NEI NIH HHS [T32 EY007110, 5T32EY07110] Funding Source: Medline
- NIDDK NIH HHS [R01 DK054477, DK54477, R56 DK054477] Funding Source: Medline
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The transcriptional coactivator PPAR gamma coactivator 1 alpha (PGG1alpha) 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 (p160(MBP)) as a repressor of PGC-1alpha. The binding and repression of PGC-1alpha by p160(MBP) is disrupted by p38 MAPK phosphorylation of PGC-1alpha. Adenoviral expression of p160(MBP) 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 p160(MBP) is or recruits a direct transcriptional suppressor. Overall, these data indicate that p160(MBP) is a powerful negative regulator of PGC-1alpha0 function and provide a molecular mechanism for the activation of PGC-1alpha by p38 MAPK. The discovery of p160(MBP) as a PGC-1alpha regulator has important implications for the understanding of energy balance and diabetes.
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