Regulation of PUMA-α by p53 in cisplatin-induced renal cell apoptosis
Regulation of PUMA-α by p53 in cisplatin-induced renal cell apoptosis
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DOI：
10.1038/sj.onc.1209440
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发表时间：
2006-07-06
期刊：
影响因子：
8
通讯作者：
Dong, Z.
中科院分区：
文献类型：
--
作者：
Jiang, M.;Wei, Q.;Dong, Z.
肾毒性是顺铂的主要副作用，顺铂是一种广泛使用的癌症治疗药物。根据其浓度，顺铂诱导肾小管细胞坏死或凋亡，而潜在的损伤机制尚不清楚。我们最近的工作表明，p53在顺铂诱导的肾小管细胞凋亡中起着关键作用;然而，由p53引发的凋亡事件仍然难以捉摸。目前的研究已经检查了Bcl-2家族蛋白，其是可能受到p53调节的细胞凋亡的关键调节剂。顺铂治疗后，抗凋亡分子Bcl-xL的表达受到抑制，而促凋亡分子巴克的表达略有增加。令人感兴趣的是，PUMA-α，一种新鉴定的p53响应性促凋亡Bcl-2家族蛋白，被顺铂显著诱导。PUMA-α诱导在细胞凋亡的发展之前或之后。诱导的PUMA-α定位于线粒体中，并且似乎通过分子相互作用拮抗Bcl-xL。pifithrin-alpha（一种p53的药理学抑制剂）可减弱顺铂治疗期间的PUMA-α诱导，并伴有Bax活化、细胞色素c释放和细胞凋亡的改善。此外，PUMA-α诱导被显性负性p53抑制。重要的是，PUMA-α敲除细胞中顺铂诱导的细胞凋亡得到改善。在体内，顺铂诱导肾脏中的PUMA-α，并且在p53缺陷动物中诱导反应被消除。总之，这项研究已经证明了第一个令人信服的证据表明，在顺铂肾毒性过程中，PUMA-α参与p53介导的肾细胞凋亡。
Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Depending on its concentration, cisplatin induces necrosis or apoptosis of tubular cells in the kidneys, whereas the underlying injury mechanism is unclear. Our recent work has suggested a critical role for p53 in cisplatin-induced tubular cell apoptosis; nevertheless, the apoptotic events triggered by p53 remain elusive. The current study has examined Bcl-2 family proteins, critical regulators of apoptosis that may be subjected to p53 regulation. Following cisplatin treatment, the expression of Bcl-xL, an antiapoptotic molecule, was suppressed, while the expression of Bak, a proapoptotic molecule, increased slightly. Of interest, PUMA-alpha, a newly identified p53-responsive proapoptotic Bcl-2 family protein, was drastically induced by cisplatin. PUMA-alpha induction preceded or paralleled the development of apoptosis. Induced PUMA-alpha was localized in mitochondria and appeared to antagonize Bcl-xL via molecular interaction. PUMA-alpha induction during cisplatin treatment was attenuated by pifithrin-alpha, a pharmacological inhibitor of p53, which was accompanied by the amelioration of Bax activation, cytochrome c release and apoptosis. Moreover, PUMA-alpha induction was suppressed by dominant-negative p53. Importantly, cisplatin-induced apoptosis was ameliorated in PUMA-alpha knockout cells. In vivo, cisplatin induced PUMA-alpha in the kidneys, and the inductive response was abrogated in p53-deficient animals. Together, this study has demonstrated the first compelling evidence for the involvement of PUMA-alpha in p53-mediated renal cell apoptosis during cisplatin nephrotoxicity.