Activation of Nrf2 in the liver is associated with stress resistance mediated by suppression of the growth hormone-regulated STAT5b transcription factor.
Activation of Nrf2 in the liver is associated with stress resistance mediated by suppression of the growth hormone-regulated STAT5b transcription factor.
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DOI：
10.1371/journal.pone.0200004
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Corton JC
中科院分区：
文献类型：
--
作者：
Rooney J;Oshida K;Vasani N;Vallanat B;Ryan N;Chorley BN;Wang X;Bell DA;Wu KC;Aleksunes LM;Klaassen CD;Kensler TW;Corton JC
转录因子Nrf 2（由Nfe 2l 2编码）诱导许多解毒和抗氧化基因的表达，以响应氧化应激。细胞质蛋白Keap 1与Nrf 2相互作用并抑制Nrf 2功能。开发了计算方法来鉴定调节小鼠肝脏基因表达纲要中Nrf 2的因子。48个Nrf 2生物标志物基因是使用小鼠肝脏中的图谱鉴定的，其中Nrf 2在Keap 1-null小鼠中被遗传激活或通过Nrf 2信号传导的有效激活剂被化学激活。使用基于秩的Running Fisher统计检验来确定Nrf 2生物标志物基因与具有已知Nrf 2激活状态的81个谱的测试集之间的相关性，证明平衡准确度为96%。对于纲要中检查的大量因素，我们发现Nrf 2的激活与通过抑制男性特异性生长激素（GH）调节的转录因子STAT 5 b的肝脏转录组女性化之间存在一致的关系。在未处理或化学处理的条件下，雌性小鼠的肝脏表现出比雄性小鼠更高的Nrf 2活化。在雄性小鼠中，Nrf 2通过乙炔雌二醇治疗被激活，而在雌性小鼠中，Nrf 2通过睾酮治疗被抑制。Nrf 2在5种含有Pit 1、Prop 1、Ghrh、Ghrhr和Ghr突变的GH信号传导中断模型中被激活。在59种激活Nrf 2的化学处理中，36种在雄性肝脏中表现出STAT 5 b抑制。在化学处理的体外比较中不存在Nrf 2-STAT 5 b偶联。用11种诱导氧化应激的化学物质处理雄性和雌性小鼠，导致雌性小鼠Nrf 2的激活程度高于雄性小鼠。女性中Nrf 2活化的基础和诱导水平相对于男性增强，为女性与男性相比对年龄依赖性疾病和化学诱导毒性的更大抗性提供了分子解释。
The transcription factor Nrf2 (encoded by Nfe2l2) induces expression of numerous detoxifying and antioxidant genes in response to oxidative stress. The cytoplasmic protein Keap1 interacts with and represses Nrf2 function. Computational approaches were developed to identify factors that modulate Nrf2 in a mouse liver gene expression compendium. Forty-eight Nrf2 biomarker genes were identified using profiles from the livers of mice in which Nrf2 was activated genetically in Keap1-null mice or chemically by a potent activator of Nrf2 signaling. The rank-based Running Fisher statistical test was used to determine the correlation between the Nrf2 biomarker genes and a test set of 81 profiles with known Nrf2 activation status demonstrating a balanced accuracy of 96%. For a large number of factors examined in the compendium, we found consistent relationships between activation of Nrf2 and feminization of the liver transcriptome through suppression of the male-specific growth hormone (GH)-regulated transcription factor STAT5b. The livers of female mice exhibited higher Nrf2 activation than male mice in untreated or chemical-treated conditions. In male mice, Nrf2 was activated by treatment with ethinyl estradiol, whereas in female mice, Nrf2 was suppressed by treatment with testosterone. Nrf2 was activated in 5 models of disrupted GH signaling containing mutations in Pit1, Prop1, Ghrh, Ghrhr, and Ghr. Out of 59 chemical treatments that activated Nrf2, 36 exhibited STAT5b suppression in the male liver. The Nrf2-STAT5b coupling was absent in in vitro comparisons of chemical treatments. Treatment of male and female mice with 11 chemicals that induce oxidative stress led to activation of Nrf2 to greater extents in females than males. The enhanced basal and inducible levels of Nrf2 activation in females relative to males provides a molecular explanation for the greater resistance often seen in females vs. males to age-dependent diseases and chemical-induced toxicity.
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影响因子：
3.8
作者：
Du, Kuo;Williams, C. David;McGill, Mitchell R.;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut
DOI：
10.1124/jpet.109.162271
发表时间：
2010-04-01
影响因子：
3.5
作者：
Aleksunes, Lauren M.;Reisman, Scott A.;Klaassen, Curtis D.
通讯作者：
Klaassen, Curtis D.
影响因子：
17.1
作者：
Axelsson, Annika S.;Tubbs, Emily;Rosengren, Anders H.
通讯作者：
Rosengren, Anders H.
影响因子：
56.9
作者：
Darnell, JE
通讯作者：
Darnell, JE
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y