The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to bax conformational change and cell death
The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to bax conformational change and cell death
复制标题
DOI：
10.1016/j.molcel.2005.05.010
复制
发表时间：
2005-06-10
期刊：
影响因子：
16
通讯作者：
Neel, BG
中科院分区：
文献类型：
--
作者：
Baksh, S;Tommasi, S;Neel, BG
肿瘤细胞通常抵抗死亡受体诱导的程序性细胞死亡（细胞凋亡）。激活的死亡受体引起 Bax 构象变化、细胞色素 c 释放和细胞死亡。我们报告说，肿瘤抑制基因 RASSF1A 是死亡受体诱导的 Bax 构象变化和细胞凋亡所必需的。 TNF α 或 TRAIL 刺激诱导 RASSF1A 和 MAP-1 募集至受体复合物，并促进 RASSF1A 和 BH3 样蛋白 MAP-1 之间的复合物形成。通常，MAP-1 受到分子内相互作用的抑制。 RASSF1A/MAP-1 结合缓解了这种抑制性相互作用，导致 MAP-1 与 Bax 结合。删除 RASSF1A 基因或短发夹沉默 RASSF1A 或 MAP-1 表达可阻断 MAP-1/Bax 相互作用、Bax 构象变化和线粒体膜插入、细胞色素 c 释放以及响应死亡受体的细胞凋亡。我们的研究结果确定 RASSF1A 和 MAP-1 是死亡受体和细胞凋亡机制之间的重要组成部分，并揭示了肿瘤抑制和死亡受体信号传导之间的潜在联系。
Tumor cells typically resist programmed cell death (apoptosis) induced by death receptors. Activated death receptors evoke Bax conformational change cytochrome c release, and cell death. We report that the tumor suppressor gene RASSF1A is required for death receptor-induced Bax conformational change and apoptosis. TNF alpha or TRAIL stimulation induced recruitment of RASSF1A and MAP-1 to receptor complexes and promoted complex formation between RASSF1A and the BH3-like protein MAP-1. Normally, MAP-1 is inhibited by an intramolecular interaction. RASSF1A/MAP-1 binding relieved this inhibitory interaction, resulting in MAP-1 association with Bax. Deletion of the RASSF1A gene or short hairpin silencing of either RASSF1A or MAP-1 expression blocked MAP-1/Bax interaction, Bax conformational change and mitochondrial membrane insertion, cytochrome c release, and apoptosis in response to death receptors. Our findings identify RASSF1A and MAP-1 as important components between death receptors and the apoptotic machinery and reveal a potential link between tumor suppression and death receptor signaling.