Oxidative stress induces p53-mediated apoptosis in glia: p53 transcription-independent way to die
Oxidative stress induces p53-mediated apoptosis in glia: p53 transcription-independent way to die
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DOI：
10.1002/jnr.10822
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发表时间：
2004-01-01
影响因子：
4.2
通讯作者：
Marlier, LNJL
中科院分区：
文献类型：
--
作者：
Bonini, P;Cicconi, S;Marlier, LNJL
氧化应激与中风、创伤性脑损伤和影响中枢神经系统（CNS）中的神经元和神经胶质细胞的神经退行性疾病的发病机制有关。肿瘤抑制蛋白p53在氧化应激引发的神经元凋亡中起着关键作用。我们研究了p53的作用和相关的分子机制，支持氧化应激诱导的神经胶质细胞凋亡。为此，我们暴露C6胶质瘤细胞和原代培养的大鼠皮质星形胶质细胞的H2 O2诱导的氧化应激协议，然后恢复期。我们评估了匹非林-α（PF-α）的作用，据报道，它可以通过特异性抑制p53 DNA结合活性来保护神经元免受缺血性损伤。值得注意的是，PF-α不能阻止氧化应激诱导的星形胶质细胞凋亡。我们证明，p53是能够介导的直接信号在线粒体的凋亡反应，尽管它的转录活性。z-VAD-fmk敏感性凋亡反应需要半胱天冬酶依赖性MDM-2降解，导致p53线粒体靶向伴随细胞色素c释放和核小体片段化。(C)2003 Wiley-Liss，Inc.
Oxidative stress has been implicated in the pathogenesis of stroke, traumatic brain injuries, and neurodegenerative diseases affecting both neuronal and glial cells in the central nervous system (CNS). The tumor suppressor protein p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress. We investigated the role of p53 and related molecular mechanisms that support oxidative stress-induced apoptosis in glia. For this purpose, we exposed C6 glioma cells and primary cultures of rat cortical astrocytes to an H2O2-induced oxidative stress protocol followed by a recovery period. We evaluated the effects of pifithrin-alpha (PF-alpha), which has been reported to protect neurons from ischemic insult by specifically inhibiting p53 DNA-binding activity. Strikingly, PF-alpha was unable to prevent oxidative stress-induced astrocyte apoptosis. We demonstrate that p53 is able to mediate an apoptotic response by direct signaling at mitochondria, despite its transcriptional activity. The z-VAD-fmk-sensitive apoptotic response requires a caspase-dependent MDM-2 degradation, leading to p53 mitochondrial targeting accompanied by cytochrome c release and nucleosomal fragmentation. (C) 2003 Wiley-Liss, Inc.