PMID:14744933

Citation	Fan, M, Rhee, J, St-Pierre, J, Handschin, C, Puigserver, P, Lin, J, Jäeger, S, Erdjument-Bromage, H, Tempst, P and Spiegelman, BM (2004) Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK. Genes Dev. 18:278-89
Abstract	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.
Links	PubMed PMC338281 Online version:10.1101/gad.1152204
Keywords	Animals; Carrier Proteins/metabolism; Carrier Proteins/pharmacology; Cell Respiration; Cells, Cultured; Energy Metabolism; Gene Expression Regulation; MAP Kinase Signaling System; Mitochondria, Muscle/metabolism; Mitogen-Activated Protein Kinases/metabolism; Muscle, Skeletal/metabolism; Nuclear Proteins/metabolism; Nuclear Proteins/pharmacology; Nucleocytoplasmic Transport Proteins; Receptors, Cytoplasmic and Nuclear/metabolism; Repressor Proteins/pharmacology; Transcription Factors/metabolism; Transcription, Genetic; Transfection; p38 Mitogen-Activated Protein Kinases
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