Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling
Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling
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DOI：
10.1038/onc.2008.188
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发表时间：
2008-10-02
期刊：
影响因子：
8
通讯作者：
Reddy, S. P.
中科院分区：
文献类型：
--
作者：
Reddy, N. M.;Kleeberger, S. R.;Reddy, S. P.
Nrf 2的遗传破坏极大地增强了对促氧化剂和致癌物诱导的各种人类疾病实验模型的易感性;但这种转录因子赋予保护的机制尚不清楚。使用Nrf 2-proficient（Nrf 2（+/+））和Nrf 2-deficient（Nrf 2（-/-））原代上皮培养物作为模型，我们现在表明Nrf 2缺乏导致氧化应激和DNA损伤，伴随着细胞周期进展的损害，主要是G（2）/M期停滞。N-乙酰半胱氨酸和谷胱甘肽（GSH）的补充消除了Nrf 2（-/-）细胞中的DNA损伤和DNA损伤反应途径;然而，只有GSH可以挽救受损的促有丝分裂因子共定位和生长停滞。Nrf 2（-/-）细胞中Akt的激活被解除，但补充GSH后Akt的激活得以恢复，抑制Akt的信号转导可显著降低GSH诱导的Nrf 2（-/-）细胞增殖和野生型细胞增殖。GSH耗竭可损害Nrf 2（+/+）细胞中Akt信号传导和促有丝分裂因子的共定位。总的来说，我们的研究结果揭示了Nrf 2在调节氧化应激诱导的细胞周期阻滞，特别是G（2）/M-检查点阻滞和增殖中的新功能，而GSH调节的氧化还原信号和Akt是这一过程所必需的。
Genetic disruption of Nrf2 greatly enhances susceptibility to prooxidant- and carcinogen-induced experimental models of various human disorders; but the mechanisms by which this transcription factor confers protection are unclear. Using Nrf2-proficient (Nrf2(+/+)) and Nrf2-deficient (Nrf2(-/-)) primary epithelial cultures as a model, we now show that Nrf2 deficiency leads to oxidative stress and DNA lesions, accompanied by impairment of cell-cycle progression, mainly G(2)/M-phase arrest. Both N-acetylcysteine and glutathione (GSH) supplementation ablated the DNA lesions and DNA damage-response pathways in Nrf2(-/-) cells; however only GSH could rescue the impaired colocalization of mitosis-promoting factors and the growth arrest. Akt activation was deregulated in Nrf2(-/-) cells, but GSH supplementation restored it. Inhibition of Akt signaling greatly diminished the GSH-induced Nrf2(-/-) cell proliferation and wild-type cell proliferation. GSH depletion impaired Akt signaling and mitosis-promoting factor colocalization in Nrf2(+/+) cells. Collectively, our findings uncover novel functions for Nrf2 in regulating oxidative stress-induced cell-cycle arrest, especially G(2)/M-checkpoint arrest, and proliferation, and GSH-regulated redox signaling and Akt are required for this process.