Hsp27 inhibits Bax activation and apoptosis via a phosphatidylinositol 3-kinase-dependent mechanism
Hsp27 inhibits Bax activation and apoptosis via a phosphatidylinositol 3-kinase-dependent mechanism
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DOI：
10.1074/jbc.m801291200
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发表时间：
2008-05-02
影响因子：
4.8
通讯作者：
Borkan, Steven C.
中科院分区：
文献类型：
--
作者：
Havasi, Andrea;Li, Zhijian;Borkan, Steven C.
Hsp27 通过未知机制抑制正常细胞和癌细胞中的线粒体损伤和细胞凋亡。为了检验 Hsp27 通过抑制 Bax 减少细胞凋亡的假设，在短暂的代谢应激（一种激活 Bax、诱导线粒体损伤并导致细胞凋亡的损伤）之前，在肾上皮细胞中操纵 Hsp27 的表达。与对照相比，增强的 Hsp27 表达抑制了构象 Bax 激活、寡聚化和向线粒体的易位，减少了细胞色素 c 和凋亡诱导因子的渗漏，并显着提高了应激后细胞存活率 > 50%。相反，使用 RNA 介导的干扰下调 Hsp27 会促进 Bax 激活、增加 Bax 易位并减少应激后的细胞存活率。免疫沉淀法在应激之前、期间或之后未检测到 Hsp27-Bax 相互作用，表明 Hsp27 间接抑制 Bax。 During stress, Hsp27 expression prevented the inactivation of Akt, a pro-survival kinase, and increased the interaction between Akt and Bax, an Akt substrate.相反，Hsp27 RNA 介导的干扰促进了应激期间 Akt 失活。 Hsp27 上调或下调显着改变磷脂酰肌醇 3-激酶（PI3-激酶）（Akt 的主要调节因子）的活性。此外，不同的 PI3 激酶抑制剂完全消除了 Hsp27 表达对 Akt 激活、Bax 失活和细胞存活的保护作用。这些数据表明，Hsp27 通过 PI3 激酶依赖性机制促进 Akt 激活，从而拮抗 Bax 介导的线粒体损伤和细胞凋亡。
Hsp27 inhibits mitochondrial injury and apoptosis in both normal and cancer cells by an unknown mechanism. To test the hypothesis that Hsp27 decreases apoptosis by inhibiting Bax, Hsp27 expression was manipulated in renal epithelial cells before transient metabolic stress, an insult that activates Bax, induces mitochondrial injury, and causes apoptosis. Compared with control, enhanced Hsp27 expression inhibited conformational Bax activation, oligomerization, and translocation to mitochondria, reduced the leakage of both cytochrome c and apoptosis-inducing factor, and significantly improved cell survival by > 50% after stress. In contrast, Hsp27 down-regulation using RNA-mediated interference promoted Bax activation, increased Bax translocation, and reduced cell survival after stress. Immunoprecipitation did not detect Hsp27-Bax interaction before, during, or after stress, suggesting that Hsp27 indirectly inhibits Bax. During stress, Hsp27 expression prevented the inactivation of Akt, a pro-survival kinase, and increased the interaction between Akt and Bax, an Akt substrate. In contrast, Hsp27 RNA-mediated interference promoted Akt inactivation during stress. Hsp27 up-or down-regulation markedly altered the activity of phosphatidylinositol 3-kinase (PI3-kinase), a major regulator of Akt. Furthermore, distinct PI3-kinase inhibitors completely abrogated the protective effect of Hsp27 expression on Akt activation, Bax inactivation, and cell survival. These data show that Hsp27 antagonizes Bax-mediated mitochondrial injury and apoptosis by promoting Akt activation via a PI3-kinase-dependent mechanism.