Hepatic oxidative stress activates the Gadd45b gene by way of degradation of the transcriptional repressor STAT3.
Hepatic oxidative stress activates the Gadd45b gene by way of degradation of the transcriptional repressor STAT3.
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DOI：
10.1002/hep.26683
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发表时间：
2014-02
期刊：
影响因子：
13.5
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
--
作者：
Kim, Jung-Hwan;Qu, Aijuan;Reddy, Janardan K.;Gao, Bin;Gonzalez, Frank J.
GADD 45 b在细胞周期阻滞、DNA修复、细胞存活、凋亡和衰老等细胞内事件中发挥重要作用。然而，其转录调控机制仍不清楚。本研究探讨了增殖物激活受体α（proliferator-activated receptor α，PPAR α）配体诱导小鼠肝脏Gadd45b基因表达的机制。在野生型小鼠中，PPAR α激动剂Wy-14，643可显著诱导Gadd45 b mRNA的表达，但在Ppara缺失小鼠中则无此作用。STAT3通过与上游调控元件结合而成为Gadd45b基因的阻遏物。使用肝脏特异性Stat3缺失小鼠证实了STAT3在Gadd45 b控制中的作用。Wy-14，643处理刺激STAT3泛素化，导致Gadd45b基因的活化，这是由于STAT3失去Gadd45b抑制的结果。STAT3降解是由PPAR α靶基因编码酶ACOX1的强制过表达诱导的，ACOX1产生增加的H2O2作为脂肪酸β-氧化的副产物。H_2O_2也刺激培养细胞中Gadd45b的表达。这些研究表明，由于氧化应激的升高，PPAR α通过促进阻遏物STAT3的降解间接诱导肝脏中的Gadd45b基因。
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.
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影响因子：
4.7
作者：
Hays, T;Rusyn, I;Peters, JM
通讯作者：
Peters, JM
影响因子：
11.4
作者：
Müller, S;Matunis, MJ;Dejean, A
通讯作者：
Dejean, A
影响因子：
21.3
作者：
Papa, S;Zazzeroni, F;Franzoso, G
通讯作者：
Franzoso, G
影响因子：
12.4
作者：
Troyano, A;Sancho, P;Aller, P
通讯作者：
Aller, P
DOI：
10.1621/nrs.08002
发表时间：
2010-04-16
期刊：
Nuclear receptor signaling
影响因子：
--
作者：
Pyper, Sean R;Viswakarma, Navin;Reddy, Janardan K
通讯作者：
Reddy, Janardan K