The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria
The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria
复制标题
DOI：
10.1074/jbc.m108975200
复制
发表时间：
2002-04-19
影响因子：
4.8
通讯作者：
Gotoh, Y
中科院分区：
文献类型：
--
作者：
Tsuruta, F;Masuyama, N;Gotoh, Y
Bax 是 Bcl-2 家族的促凋亡成员，主要定位于细胞质，但响应凋亡刺激重新分布到线粒体，诱导细胞色素 c 释放。在这项研究中，我们证明磷脂酰肌醇 3-OH 激酶 (PI3K)-Akt 通路在 Bax 亚细胞定位的调节中发挥重要作用。我们发现，PI3K 抑制剂 LY294002 阻断血清的作用，防止 Bax 易位至线粒体，并且 PI3K 活性形式的表达抑制星形孢菌素诱导的 Bax 易位，表明 PI3K 活性对于将 Bax 保留在细胞质中至关重要。相比之下，MEK 抑制剂 U0126 和活性 MEK 对 Bax 定位几乎没有影响。关于 PI3K 的下游效应子，我们发现活性 Akt 的表达（而非血清和糖皮质激素诱导的蛋白激酶 (SGK)）抑制星形孢菌素诱导的 Bax 易位，而显性失活 Akt 适度促进 Bax 易位。在所用条件下，Akt 的表达不会改变 Bax、Bcl-2、Bcl-X-L 或磷酸化 JNK 的水平，表明 Akt 存在抑制 Bax 易位的替代机制。总的来说，这些结果表明 PI3K-Akt 途径抑制 Bax 从细胞质到线粒体的易位，并揭示了 PI3K-Akt 途径促进存活的新机制。
Bax, a proapoptotic member of the Bcl-2 family, localizes largely in the cytoplasm but redistributes to mitochondria in response to apoptotic stimuli, where it induces cytochrome c release. In this study, we show that the phosphatidylinositol 3-OH kinase (PI3K)-Akt pathway plays an important role in the regulation of Bax subcellular localization. We found that LY294002, a PI3K inhibitor, blocked the effects of serum to prevent Bax translocation to mitochondria and that expression of an active form of PI3K suppressed staurosporine-induced Bax translocation, suggesting that PI3K activity is essential for retaining Bax in the cytoplasm. In contrast, both U0126, a MEK inhibitor, and active MEK had little effect on Bax localization. In respect to downstream effectors of PI3K, we found that expression of active Akt, but not serum and glucocorticoid-induced protein kinase (SGK), suppressed staurosporine-induced translocation of Bax, whereas dominant negative Akt moderately promoted Bax translocation. Expression of Akt did not alter the levels of Bax, Bcl-2, Bcl-X-L, or phosphorylated JNK under the conditions used, suggesting that there were alternative mechanisms for Akt in the suppression of Bax translocation. Collectively, these results suggest that the PI3K-Akt pathway inhibits Bax translocation from cytoplasm to mitochondria and have revealed a novel mechanism by which the PI3K-Akt pathway promotes survival.