Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α: Modulation by p38 MAPK

Melina Fan, James Rhee, Julie St-Pierre, Christoph Handschin, Pere Puigserver, Jiandie Lin, Sibylle Jäeger, Hediye Erdjument-Bromage, Paul Tempst, Bruce M. Spiegelman

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Pages (from-to)278-289
    Number of pages12
    JournalGenes & development
    Volume18
    Issue number3
    DOIs
    StatePublished - Feb 1 2004

    Fingerprint

    PPAR gamma
    p38 Mitogen-Activated Protein Kinases
    Carrier Proteins
    Respiration
    Phosphorylation
    Muscles
    Brown Adipose Tissue
    Gluconeogenesis
    Myoblasts
    Mitogen-Activated Protein Kinase Kinases
    Organelle Biogenesis
    Electron Transport
    Adrenergic Agents
    Type 2 Diabetes Mellitus
    Chromatin
    Cytokines

    Keywords

    • Mitochondria
    • Mybbp1a
    • p38 MAPK
    • PGC-1α
    • Repressor

    ASJC Scopus subject areas

    • Genetics
    • Developmental Biology

    Cite this

    Fan, M., Rhee, J., St-Pierre, J., Handschin, C., Puigserver, P., Lin, J., ... Spiegelman, B. M. (2004). Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α: Modulation by p38 MAPK. Genes & development, 18(3), 278-289. https://doi.org/10.1101/gad.1152204

    Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α : Modulation by p38 MAPK. / Fan, Melina; Rhee, James; St-Pierre, Julie; Handschin, Christoph; Puigserver, Pere; Lin, Jiandie; Jäeger, Sibylle; Erdjument-Bromage, Hediye; Tempst, Paul; Spiegelman, Bruce M.

    In: Genes & development, Vol. 18, No. 3, 01.02.2004, p. 278-289.

    Research output: Contribution to journalArticle

    Fan, M, Rhee, J, St-Pierre, J, Handschin, C, Puigserver, P, Lin, J, Jäeger, S, Erdjument-Bromage, H, Tempst, P & Spiegelman, BM 2004, 'Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α: Modulation by p38 MAPK', Genes & development, vol. 18, no. 3, pp. 278-289. https://doi.org/10.1101/gad.1152204
    Fan, Melina ; Rhee, James ; St-Pierre, Julie ; Handschin, Christoph ; Puigserver, Pere ; Lin, Jiandie ; Jäeger, Sibylle ; Erdjument-Bromage, Hediye ; Tempst, Paul ; Spiegelman, Bruce M. / Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α : Modulation by p38 MAPK. In: Genes & development. 2004 ; Vol. 18, No. 3. pp. 278-289.
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