Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics
Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics
复制标题
DOI：
10.1016/s1535-6108(02)00127-7
复制
发表时间：
2002-09-01
期刊：
影响因子：
50.3
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Letai, A;Bassik, MC;Korsmeyer, SJ
BCL-2家族的“仅BH 3”蛋白需要“多结构域”促凋亡成员BAX和巴克从线粒体释放细胞色素c并杀死细胞。我们发现代表BID或BIM的α-螺旋BH 3结构域的短肽能够诱导巴克和BAX的寡聚化以释放细胞色素c。以来自BAD和BIK的BH 3肽为特征的另一个子集不能直接激活BAX、巴克，而是结合抗凋亡BCL-2，导致BID样BH 3结构域的置换，从而引发线粒体功能障碍。转导的BAD样和BID样BH 3肽也显示出协同作用，杀死白血病细胞。这些数据支持BH 3结构域的两类模型：“激活”BAX、巴克的BID样结构域和通过占据抗凋亡成员的口袋“致敏”的BAD样结构域。
The "BH3-only" proteins of the BCL-2 family require "multidomain" proapoptotic members BAX and BAK to release cytochrome c from mitochondria and kill cells. We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. Another subset characterized by the BH3 peptides from BAD and BIK cannot directly activate BAX, BAK but instead binds antiapoptotic BCL-2, resulting in the displacement of BID-like BH3 domains that initiate mitochondrial dysfunction. Transduced BAD-like and BID-like BH3 peptides also displayed synergy in killing leukemic cells. These data support a two-class model for BH3 domains: BID-like domains that "activate" BAX, BAK and BAD-like domains that "sensitize" by occupying the pocket of antiapoptotic members.