APE1 promotes antioxidant capacity by regulating Nrf-2 function through a redox-dependent mechanism.
APE1 promotes antioxidant capacity by regulating Nrf-2 function through a redox-dependent mechanism.
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DOI：
10.1016/j.freeradbiomed.2014.10.007
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发表时间：
2015
影响因子：
7.4
通讯作者：
Jin-lu Shan;Hai-Tao He;Mengxia Li;Jianhua Zhu;Yi Cheng;Nan Hu;Ge Wang;Dong Wang;Xue-qin Yang;Yong He;Hualiang Xiao;W. Tong;Zhenzhou Yang
中科院分区：
文献类型：
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作者：
Jin-lu Shan;Hai-Tao He;Mengxia Li;Jianhua Zhu;Yi Cheng;Nan Hu;Ge Wang;Dong Wang;Xue-qin Yang;Yong He;Hualiang Xiao;W. Tong;Zhenzhou Yang
APE1是一种多功能蛋白质，最近被认为可以保护细胞免受氧化应激的伤害。在本研究中，我们利用ape1功能突变体证实了ape1׳S对细胞抗氧化能力的影响与其氧化还原活性有关，并探讨了该多功能蛋白影响转录因子nrf-2调控氧化应激诱导基因功能的机制。利用一对同时具有氧化还原活性和乙酰化调节活性的突变体，体外实验表明，APE1的氧化还原活性对于其与NRF-2的核结合以及随后在氧化挑战过程中激活NRF-2׳S转录的下游几个基因是至关重要的。重要的氧化应激基因受APE1氧化还原活性的影响，包括Hmox1、GSTM1和Txnrd1。此外，利用人非小细胞肺癌组织样本以及裸鼠异种移植模型，我们确定APE1的表达水平与体内的氧化应激呈负相关。这些发现表明，干扰ape1的这些重要功能在预防某些放射治疗的耐药性方面是有希望的，需要进一步的研究来理解ape1׳S在调节细胞环境的基础氧化还原状态和氧化应激状态中的复杂作用。
APE1 is a multifunctional protein that has recently been implicated in protecting cells from oxidative stress. In the current study, we confirmed that APE1׳s effect on cellular antioxidant capacity is related to its redox activity through the use of an APE1 functional mutant, and we investigated the mechanism through which this multifunctional protein affects the function of the transcription factor Nrf-2 in regulating oxidative stress-induced genes. Using a pair of mutants for both the redox activity and the acetylation-regulated activity of APE1, in vitro assays showed that the redox activity of APE1 is crucial for its nuclear association with Nrf-2 and subsequent activation of Nrf-2׳s transcription of several downstream genes during oxidative challenge. Important oxidative stress genes are affected by APE1 redox activity, including Hmox1, Gstm1, and Txnrd1. In addition, utilizing human non-small-cell lung cancer sample tissue as well as a nude mouse xenograft model, we determined that APE1 expression levels are inversely correlated to oxidative stress in vivo. These findings indicated that interference with these crucial functions of APE1 shows promise in preventing resistance to certain radiotherapies and that further research is necessary to understand APE1׳s complex roles in regulating both the basal redox status and the oxidative stress state of the cellular environment.