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ATF‐1 is a hypoxia responsive transcriptional activator of UCP3
Author(s) -
LU ZHONGPING,
Sack Michael N
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.184
Subject(s) - ucp3 , downregulation and upregulation , skeletal muscle , uncoupling protein , microbiology and biotechnology , phosphorylation , biology , chemistry , transcription factor , activator (genetics) , endocrinology , biochemistry , gene , adipose tissue , brown adipose tissue
Uncoupling protein 3 (UCP3) confers resilience against oxidative stress in skeletal muscle. We find a marked upregulation of UCP3 expression in response to hypoxia in mice and in skeletal myotubes. Furthermore, in primary myocytes deficient in UCP3, basal and hypoxia‐induced ROS levels are elevated. To investigate the regulation mechanism, a transcription factor transfection array of 704 full‐length cDNAs in conjunction with a murine UCP3 promoter‐luciferase construct was carried out and ATF‐1 was identified as a transcriptional activator of UCP3. Site‐directed mutagenesis and ChIP assays identify a 10 bp region necessary for ATF‐1 induction of UCP3 promoter activity. Hypoxia promotes the phosphorylation of ATF‐1 and its depletion by shRNA prevents hypoxia mediated upregulation of UCP3. Pharmacologic inhibition of p38MAP kinase prevents both hypoxia‐mediated ATF‐1 phosphorylation and UCP3 upregulation. Interestingly, neither PKA signaling nor HIF‐1a activation by cobalt chloride modulates skeletal muscle UCP3 protein levels. In conclusion these data identify that ATF‐1, via p38MAPK upregulates UCP3 expression in response to hypoxia and identifies a novel regulatory program orchestrating skeletal muscle anti‐oxidant defense. Funded by Intramural Research of NHLBI/NIH.