A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways
A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways
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DOI：
10.1038/onc.2009.293
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发表时间：
2009-12-17
期刊：
影响因子：
8
通讯作者：
Cartwright, C. A.
中科院分区：
文献类型：
--
作者：
Mamidipudi, V.;Cartwright, C. A.
早些时候我们发现 RACK1 通过抑制 G(1) 和有丝分裂检查点的 Src 活性来调节人类结肠细胞的生长。在这里，我们发现 RACK1 还可以部分通过抑制 Src 来诱导细胞凋亡。在内在途径中，RACK1抑制抗凋亡Bcl-2和Bcl-X-L的表达，诱导促凋亡Bim的表达，将Bim和Bax靶向线粒体，诱导Bax寡聚化（这需要Bim和Src的抑制），使线粒体膜去极化，释放细胞色素c，并激活caspases-9和-3以及死亡底物。 Bax 和 Bim 是 RACK1 介导的线粒体细胞死亡所必需的。 RACK1 诱导的 Bax 寡聚化是十字孢菌素介导的细胞死亡所必需的。 RACK1 还通过阻断 Akt 细胞存活途径的 Src 激活来诱导细胞凋亡。这会导致转录因子 FOXO3 的激活，FOXO3 是细胞凋亡和 G(1) 停滞的有效诱导剂。总的来说，我们的结果表明，RACK1 部分通过抑制 Src 来促进线粒体细胞死亡并阻止 Akt 介导的细胞存活。因此，RACK1 抑制结肠细胞的生长并诱导其死亡。利用这些双重功能可能会产生模仿 RACK1 功能的新型结肠癌疗法。癌基因 (2009) 28, 4421-4433; doi：10.1038/onc.2009.293； 2009 年 9 月 21 日在线发布
Earlier we showed that RACK1 regulates growth of human colon cells by suppressing Src activity at G(1) and mitotic checkpoints. Here, we show that RACK1 also induces apoptosis of the cells, partly by inhibiting Src. In the intrinsic pathway, RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X-L, induces expression of proapoptotic Bim, targets Bim and Bax to the mitochondria, induces oligomerization of Bax (which requires Bim and inhibition of Src), depolarizes mitochondria membranes, releases cytochrome c, and activates caspases-9 and -3 and death substrates. Bax and Bim are required for RACK1-mediated mitochondrial cell death. RACK1-induced oligomerization of Bax is required for staurosporine-mediated cell death. RACK1 also induces apoptosis by blocking Src activation of the Akt cell survival pathway. This leads to activation of the transcription factor FOXO3, a potent inducer of apoptosis and G(1) arrest. Collectively, our results show that RACK1, partly by inhibiting Src, promotes mitochondrial cell death and blocks Akt-mediated cell survival. Thus, RACK1 inhibits growth and induces death of colon cells. Exploitation of these dual functions could lead to novel colon cancer therapies that mimic RACK1 function. Oncogene (2009) 28, 4421-4433; doi:10.1038/onc.2009.293; published online 21 September 2009