Hepatic oxidative stress activates the Gadd45b gene by way of degradation of the transcriptional repressor STAT3.
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 peroxisome proliferator-activated receptor α (PPARα) ligand induction of the Gadd45b gene in mouse liver was investigated. Gadd45b messenger RNA (mRNA) was markedly induced by the PPARα agonist Wy-14,643 in wild-type mice but not in Ppara-null mice. Signal transducer and activator of transcription 3 (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, which produces increased H(2)O(2) as a byproduct of fatty acid β-oxidation. H(2)O(2) also stimulated expression of Gadd45b in cultured cells.


CONCLUSIONS
PPARα indirectly induces the Gadd45b gene in liver through promoting degradation of the repressor STAT3 as a result of elevated oxidative stress.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Jung-Hwan
JH
Kim
Aijuan
A
Qu
Janardan K
JK
Reddy
Bin
B
Gao
Frank J
FJ
Gonzalez
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018384:Oxidative Stress / Q000502:physiology*; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D006861:Hydrogen Peroxide; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins; C494087:Stat3 protein, mouse; C006253:pirinixic acid