한빛사논문
- 조회3,036
Abstract
Jung-Hwan Kim1, Aijuan Qu1, Janardan K. Reddy2, Bin Gao3, Frank J. Gonzalez1,*
1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
2 Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
3 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
*Correspondence: Frank J. Gonzalez
ABSTRACT
Growth arrest and DNA damage-inducible beta (GADD45b) plays an important role in many intracellular events, such as cell cycle arrest, DNA repair, cell survival, apoptosis and senescence. However, its mechanism of transcriptional regulation remains unclear. In this study, the mechanism of proliferator-activated receptor α (PPARα) ligand induction of the Gadd45b gene in mouse liver was investigated. Gadd45b mRNA was markedly induced by the PPARα agonist, Wy-14,643, in wild-type mice but not in Ppara-null mice. STAT3 was found to be a repressor of the Gadd45b gene through binding to upstream regulatory elements. The role of STAT3 in control of Gadd45b was confirmed using liver-specific Stat3-null mice. Wy-14,643 treatment stimulated STAT3 ubiquitination leading to activation of the Gadd45b gene as a result of loss of Gadd45b repression by STAT3. STAT3 degradation was induced by forced overexpression of the PPARα target gene-encoded enzyme ACOX1, that produces increased H2O2 as a by product of fatty acid β-oxidation. H2O2 also stimulated expression of Gadd45b in cultured cells. These studies revealed that PPARα indirectly induces the Gadd45b gene in liver through promoting degradation of the repressor STAT3 as a result of elevated oxidative stress. (Hepatology 2013;)
Keywords: PPARα; GADD45b; STAT3; ACOX1
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.26683
논문정보
- Research article
- 2013년 08월 (BRIC 등록일 2013-09-09)
- 국외 연구진
- 의약학 > 약학
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