title: Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK.
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.
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Melina
authors.initials: M
authors.lastname: Fan
authors.forename: James
authors.initials: J
authors.lastname: Rhee
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.forename: Jiandie
authors.initials: J
authors.lastname: Lin
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jäeger
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology*; D019069:Cell Respiration; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D008931:Mitochondria, Muscle / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism / Q000494:pharmacology*; D029543:Nucleocytoplasmic Transport Proteins; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491719:MYBBP1A protein, human; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases