Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation
Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation
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DOI：
10.1038/nchembio809
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发表时间：
2006-09-01
影响因子：
14.8
通讯作者：
Gudkov, Andrei V.
中科院分区：
文献类型：
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作者：
Strom, Evguenia;Sathe, Swati;Gudkov, Andrei V.
p53依赖性细胞凋亡有助于癌症治疗的副作用，并且p53功能的遗传或药理学抑制可以增加正常组织对遗传毒性应激的抗性（1-6）。最近已经表明，p53可以通过不依赖于反式激活而是涉及p53易位到线粒体的机制诱导细胞凋亡（7-13）。为了确定这种p53活性对正常组织放射敏感性的影响，我们分离出一种名为pifithrin-mu（PFT mu，1）的小分子，通过降低其与抗凋亡蛋白Bcl-xL和Bcl-2的亲和力来抑制p53与线粒体的结合，但对p53依赖性反式激活没有影响。PFT mu对p53具有高度特异性，并且不能保护细胞免受促凋亡蛋白Bax过度表达或地塞米松处理诱导的细胞凋亡（2）。PFT mu从辐射引起的p53介导的凋亡中拯救原代小鼠胸腺细胞，并保护小鼠免受导致致死性造血综合征的辐射剂量。这些结果表明，选择性抑制p53途径的线粒体分支足以在体内进行辐射防护。
p53-dependent apoptosis contributes to the side effects of cancer treatment, and genetic or pharmacological inhibition of p53 function can increase normal tissue resistance to genotoxic stress(1-6). It has recently been shown that p53 can induce apoptosis through a mechanism that does not depend on transactivation but instead involves translocation of p53 to mitochondria(7-13). To determine the impact of this p53 activity on normal tissue radiosensitivity, we isolated a small molecule named pifithrin-mu (PFT mu, 1) that inhibits p53 binding to mitochondria by reducing its affinity to antiapoptotic proteins Bcl-xL and Bcl-2 but has no effect on p53-dependent transactivation. PFT mu has a high specificity for p53 and does not protect cells from apoptosis induced by overexpression of proapoptotic protein Bax or by treatment with dexamethasone (2). PFT mu rescues primary mouse thymocytes from p53-mediated apoptosis caused by radiation and protects mice from doses of radiation that cause lethal hematopoietic syndrome. These results indicate that selective inhibition of the mitochondrial branch of the p53 pathway is sufficient for radioprotection in vivo.