Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α: Modulation by p38 MAPK Journal Article
| Authors: | Fan, M.; Rhee, J.; St-Pierre, J.; Handschin, C.; Puigserver, P.; Lin, J.; Jäeger, S.; Erdjument-Bromage, H.; Tempst, P.; Spiegelman, B. M. |
| Article Title: | Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α: Modulation by p38 MAPK |
| Abstract: | The transcriptional coactivator PPAR gamma coactivator 1 α (PGC-1α) is a key regulator of metabolic processes such as mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver. Reduced levels of PGC-1α in humans have been associated with type II diabetes. PGC-1α contains a negative regulatory domain that attenuates its transcriptional activity. This negative regulation is removed by phosphorylation of PGC-1α by p38 MAPK, an important kinase downstream of cytokine signaling in muscle and β-adrenergic signaling in brown fat. We describe here the identification of p160 myb binding protein (p160 MBP) as a repressor of PGC-1α. The binding and repression of PGC-1α by p160MBP is disrupted by p38 MAPK phosphorylation of PGC-1α. Adenoviral expression of p160MBP in myoblasts strongly reduces PGC-1α'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-1α from chromatin, suggesting that p160 MBP is or recruits a direct transcriptional suppressor. Overall, these data indicate that p160MBP is a powerful negative regulator of PGC-1α function and provide a molecular mechanism for the activation of PGC-1α by p38 MAPK. The discovery of p160MBP as a PGC-1α regulator has important implications for the understanding of energy balance and diabetes. |
| Keywords: | signal transduction; mitogen activated protein kinase; controlled study; protein expression; protein phosphorylation; carrier protein; unclassified drug; nonhuman; protein domain; protein analysis; animal cell; mouse; animal; metabolism; animals; cells, cultured; map kinase signaling system; mitogen activated protein kinase p38; nuclear protein; protein binding; transcription factor; genetic transcription; transcription, genetic; transfection; animalia; transcription factors; nuclear proteins; gene expression regulation; cytokine; genetic transfection; cell culture; chromatin; carrier proteins; binding protein; mitogen-activated protein kinases; mitochondria; repressor protein; repressor proteins; peroxisome proliferator activated receptor gamma; non insulin dependent diabetes mellitus; energy metabolism; skeletal muscle; adenoviridae; protein p160; myoblast; receptors, cytoplasmic and nuclear; muscle, skeletal; adenovirus; energy balance; mitochondrial respiration; brown adipose tissue; cell receptor; electron transport; repressor; gluconeogenesis; peroxisome proliferator activated receptor gamma coactivator 1alpha; p38 mitogen-activated protein kinases; adrenergic system; p38 mapk; pgc-1α; nucleocytoplasmic transport proteins; cell respiration; priority journal; article; mybbp1a; p160 myb binding protein; p160 myb-binding protein; peroxisome proliferator activated receptor; peroxisome proliferator-activated receptor; protein mybbp1a; muscle mitochondrion; mitochondria, muscle |
| Journal Title: | Genes and Development |
| Volume: | 18 |
| Issue: | 3 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2004-02-01 |
| Start Page: | 278 |
| End Page: | 289 |
| Language: | English |
| DOI: | 10.1101/gad.1152204 |
| PROVIDER: | scopus |
| PMCID: | PMC338281 |
| PUBMED: | 14744933 |
| DOI/URL: | |
| Notes: | Genes Dev. -- Cited By (since 1996):170 -- Export Date: 16 June 2014 -- CODEN: GEDEE -- Source: Scopus |
