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RESEARCH PAPER
: modulation by p38 MAPK
1 Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA; 2 Johns Hopkins University Medical School, Baltimore, Maryland 21205, USA; 3 Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
The transcriptional coactivator PPAR gamma coactivator 1 
(PGC-1) is a key regulator of metabolic processes such as mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver. Reduced levels of PGC-1 in humans have been associated with type II diabetes. PGC-1 contains a negative regulatory domain that attenuates its transcriptional activity. This negative regulation is removed by phosphorylation of PGC-1 by p38 MAPK, an important kinase downstream of cytokine signaling in muscle and 
-adrenergic signaling in brown fat. We describe here the identification of p160 myb binding protein (p160MBP) as a repressor of PGC-1. The binding and repression of PGC-1 by p160MBP is disrupted by p38 MAPK phosphorylation of PGC-1. Adenoviral expression of p160MBP in myoblasts strongly reduces PGC-1'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-1 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-1 function and provide a molecular mechanism for the activation of PGC-1 by p38 MAPK. The discovery of p160MBP as a PGC-1 regulator has important implications for the understanding of energy balance and diabetes.
[Keywords: PGC-1; Mybbp1a; mitochondria; repressor; p38 MAPK]
Received September 15, 2003; revised version accepted December 11, 2003.
Supplemental material is available at http://www.genesdev.org.
4 Corresponding author.
E-MAIL bruce_spiegelman{at}dfci.harvard.edu; FAX (617) 632-5363.
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