The Bcl-2 proteins Noxa and Bcl-xL co-ordinately regulate oxidative stress-induced apoptosis
The Bcl-2 proteins Noxa and Bcl-xL co-ordinately regulate oxidative stress-induced apoptosis
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DOI：
10.1042/bj20112023
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发表时间：
2012-05-15
影响因子：
4.1
通讯作者：
Li, Chi
中科院分区：
文献类型：
--
作者：
Eno, Colins O.;Zhao, Guoping;Li, Chi
由于氧化应激诱导细胞凋亡的详细分子机制尚不完全清楚，我们研究了复杂的Bcl-2蛋白网络如何调节氧化应激诱导的细胞凋亡。利用mef（小鼠胚胎成纤维细胞），我们发现内源性抗凋亡Bcl-2蛋白Bcl-xL可阻止H2O2诱导的细胞凋亡。BH3 (Bcl-2同源3)-only Bcl-2蛋白Noxa是h2o2诱导的细胞死亡所必需的，是唯一的BH3-only Bcl-2蛋白，其促凋亡活性被内源性Bcl-xL完全拮抗。H2O2处理后，Noxa mRNA在BH3-only Bcl-2蛋白中增幅最大。Noxa的主要结合靶点抗凋亡Bcl-2蛋白Mcl-1（髓系细胞白血病序列1）的表达水平在h2o2处理的细胞中以Noxa依赖的方式降低，并且Mcl-1过表达能够防止h2o2诱导的bcl - xl缺陷MEF细胞死亡。重要的是，Mcl-1和Bcl-xL表达的降低引起自发性细胞死亡。这些研究揭示了H2O2激活Noxa的信号通路，在缺乏Bcl-xL表达的情况下导致Mcl-1的减少和随后的细胞死亡。本研究结果表明，抗凋亡和促凋亡的Bcl-2蛋白共同调节氧化应激诱导的细胞凋亡。
Because the detailed molecular mechanisms by which oxidative stress induces apoptosis are not completely known, we investigated how the complex Bcl-2 protein network might regulate oxidative stress-induced apoptosis. Using MEFs (mouse embryonic fibroblasts), we found that the endogenous anti-apoptotic Bcl-2 protein Bcl-xL prevented apoptosis initiated by H2O2. The BH3 (Bcl-2 homology 3)-only Bcl-2 protein Noxa was required for H2O2-induced cell death and was the single BH3-only Bcl-2 protein whose pro-apoptotic activity was completely antagonized by endogenous Bcl-xL. Upon H2O2 treatment, Noxa mRNA displayed the greatest increase among BH3-only Bcl-2 proteins. Expression levels of the anti-apoptotic Bcl-2 protein Mcl-1 (myeloid cell leukaemia sequence 1), the primary binding target of Noxa, were reduced in H2O2-treated cells in a Noxa-dependent manner, and Mcl-1 overexpression was able to prevent H2O2-induced cell death in Bcl-xL-deficient MEF cells. Importantly, reduction of the expression of both Mcl-1 and Bcl-xL caused spontaneous cell death. These studies reveal a signalling pathway in which H2O2 activates Noxa, leading to a decrease in Mcl-1 and subsequent cell death in the absence of Bcl-xL expression. The results of the present study indicate that both anti- and pro-apoptotic Bcl-2 proteins co-operate to regulate oxidative stress-induced apoptosis.