Activation of p53 and its target genes p21WAF1/Cip1 PAG608/Wig-1 in ischemic preconditioning
Activation of p53 and its target genes p21WAF1/Cip1 PAG608/Wig-1 in ischemic preconditioning
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DOI：
10.1016/s0169-328x(99)00146-1
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发表时间：
1999-07-05
期刊：
影响因子：
--
通讯作者：
Wieloch, T
中科院分区：
文献类型：
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作者：
Tomasevic, G;Shamloo, M;Wieloch, T
由双侧颈总动脉闭塞和低血压引起的大鼠短暂的3分钟整体前脑缺血，赋予海马锥体神经元抵抗随后10分钟缺血的能力，这通常对这些细胞是致命的。这种缺血预处理或耐受性的分子机制尚不清楚。肿瘤抑制因子 p53 是一种转录因子，与各种损伤（包括脑缺血）后神经元死亡有关。 p53 因细胞应激而被激活，例如缺氧和DNA损伤。利用原位杂交，我们研究了缺血预适应的双血管闭塞模型中 p53 及其两个靶基因 p21(WAF1/Cip1) 和最近克隆的 PAG608/Wig-1 的海马 mRNA 表达。我们还使用免疫组织化学评估了 p53 和 PAG608/Wig-1 蛋白水平的变化。在 3 分钟（非致死）预处理和 10 分钟（致死）非条件缺血后，缺血敏感 CAI 区域中所有三个基因的 mRNA 水平均增加。相反，在 48 小时前 3 分钟缺血损伤预处理 10 分钟缺血后，在 CA1 中没有检测到这些基因的上调。非条件缺血 10 分钟后，在海马中观察到 p53 和 PAG608/Wig-1 的神经元免疫染色增加，而在预条件缺血 3 分钟和预条件缺血 10 分钟后，这种现象不太明显。我们的结果表明，在致命性和非致命性缺血性损伤后，p53 及其反应基因 p21(WAF2/Cip1) 和 PAG608/Wig-1 的激活发生在大脑中，并且缺血预处理显着减少了这种激活。 (C) 1999 Elsevier Science B.V. 保留所有权利。
A brief, 3 min period of global forebrain ischemia in the rat, induced by bilateral common carotid occlusion combined with hypotension, confers resistance to hippocampal pyramidal neurons against a subsequent 10 min ischemia, which is normally lethal to these cells. The molecular mechanisms underlying this ischemic preconditioning, or tolerance, are poorly understood. The tumor suppressor p53 is a transcription factor implicated in neuronal death following various insults, including cerebral ischemia. p53 is activated in response to cellular stress, e.g. hypoxia and DNA damage. Using in situ hybridization, we investigated the hippocampal mRNA expression of p53, and two of its target genes, p21(WAF1/Cip1) and the recently cloned PAG608/Wig-1, in a two-vessel occlusion model of ischemic preconditioning. We also evaluated changes in the protein levels of p53 and PAG608/Wig-1 using immunohistochemistry. The mRNA levels of all three genes increased in the ischemia sensitive CAI region both following 3 min (non-lethal) preconditioning and 10 min of (lethal) nonconditioned ischemia. In contrast, after 10 min of ischemia preconditioned by a 3 min ischemic insult 48 h earlier, no upregulation of these genes was detected in the CA1. Following 10 min of nonconditioned ischemia, increased neuronal immunostaining of p53 and PAG608/Wig-1 was observed in the hippocampus, which was less pronounced following 3 min of preconditioning ischemia and 10 min of preconditioned ischemia. Our results demonstrate that activation of p53 and its response genes p21(WAF2/Cip1) and PAG608/Wig-1 occurs in the brain following lethal as well as non-lethal ischemic insults, and that ischemic preconditioning markedly diminishes this activation. (C) 1999 Elsevier Science B.V. All rights reserved.