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    Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions

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    Name:
    J. Biol. Chem.-2016-Collier-26 ...
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    Description:
    FInal Published Version
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    Author
    Collier, Justin B.
    Whitaker, Ryan M.
    Eblen, Scott T.
    Schnellmann, Rick G.
    Affiliation
    Univ Arizona
    Issue Date
    2016-12-23
    
    Metadata
    Show full item record
    Publisher
    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
    Citation
    Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions 2016, 291 (52):26850 Journal of Biological Chemistry
    Journal
    Journal of Biological Chemistry
    Rights
    © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury. We evaluated the role of ERK1/2 on the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) gene, a master regulator of mitochondrial function. The potent and specific MEK1/2 inhibitor trametinib rapidly blocked ERK1/2 phosphorylation, decreased cytosolic and nuclear FOXO3a/1 phosphorylation, and increased PGC-1 alpha gene expression and its downstream mitochondrial biogenesis (MB) targets under physiological conditions in the kidney cortex and in primary renal cell cultures. The epidermal growth factor receptor (EGFR) inhibitor erlotinib blocked ERK1/2 phosphorylation and increased PGC-1 alpha gene expression similar to treatment with trametinib, linking EGFR activation and FOXO3a/1 inactivation to the down-regulation of PGC-1 alpha and MB through ERK1/2. Pretreatment with trametinib blocked early ERK1/2 phosphorylation following ischemia/reperfusion kidney injury and attenuated the downregulation of PGC-1 alpha and downstream target genes. These results demonstrate that ERK1/2 rapidly regulates mitochondrial function through a novel pathway, EGFR/ERK1/2/FOXO3a/1/PGC-1 alpha, under physiological and pathological conditions. As such, ERK1/2 down-regulates mitochondrial function directly by phosphorylation of upstream regulators of PGC-1 alpha and subsequently decreasing MB.
    Note
    12 month embargo; Published, JBC Papers in Press, November 14, 2016,
    ISSN
    0021-9258
    1083-351X
    DOI
    10.1074/jbc.M116.754762
    Version
    Final published version
    Sponsors
    National Institutes of Health National Center for Research Resources [C06-RR015455]
    Additional Links
    http://www.jbc.org/lookup/doi/10.1074/jbc.M116.754762
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M116.754762
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