Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-XL
Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-XL
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DOI：
10.1038/sj.onc.1205270
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发表时间：
2002-03-21
期刊：
影响因子：
8
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Vieira, Helena L. A.;Boya, Patricia;Kroemer, Guido
当与Atennapedia质膜易位结构域（Ant）融合时，对应于Bax（Bcl 2BH 3）或Bcl-2（Bcl 2BH 3）的BH 3结构域的肽是细胞凋亡的有效诱导剂。Bcl 2BH 3Ant和Bcl 2BH 3Ant通过不被过表达的Bcl-2或Bcl-XL抑制的机制引起线粒体膜透化（MMP）和凋亡，但被线粒体通透性转换孔抑制剂环孢菌素A（CsA）部分抑制。当加入到分离的线粒体中时，Bcl 2BH 3和Bcl 2BH 3诱导MMP，该MMP被CsA抑制。然而，Bcl-2或Bcl-XL未能抑制MMP诱导的Bc 2BH 3和Bc 2BH 3在体外，而他们有效地抑制诱导MMP的Vpr蛋白（从人类免疫缺陷病毒-1），腺嘌呤核苷酸转运蛋白（ANT）的配体。在电生理实验中，只有Bcl 2BH 3（而不是Bcl 2BH 3）能透化ANT的脂蛋白体，并诱导ANT形成非特异性通道。相反，Bcl 2BH 3和Bcl 2BH 3都能够刺激重组Bax蛋白的通道形成。因此，ABBH 3可能通过作用于至少两个靶点ANT和ANT样蛋白来诱导MMP。相反，Bcl 2BH 3将以不依赖于ANT的方式引发MMP。在纯化的线粒体中，ANT的两个配体，bongkrekic酸和来自巨细胞病毒的蛋白质vMIA，未能阻止由Bcl 2BH 3或Bcl 2BH 3诱导的MMP。总之，Bcl-2BH 3和Bcl-2BH 3通过克服Bcl-2和Bcl-XL的细胞保护作用的机制诱导MMP和凋亡。
Peptides corresponding to the BH3 domains of Bax (BaxBH3) or Bcl-2 (Bcl2BH3) are potent inducers of apoptosis when fused to the Atennapedia plasma membrane translocation domain (Ant). BaxBH3Ant and Bcl2BH3Ant caused a mitochondrial membrane permeabilization (MMP) and apoptosis, via a mechanism that was not inhibited by overexpressed Bcl-2 or Bcl-XL, yet partially inhibited by cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition pore. When added to isolated mitochondria, BaxBH3 and Bcl2BH3 induced MMP, which was inhibited by CsA. However, Bcl-2 or Bcl-XL failed to inhibit MMP induced by BaxBH3 and Bc2BH3 in vitro, while they efficiently suppressed the induction of MMP by the Vpr protein (from human immunodeficiency virus-1), a ligand of the adenine nucleotide translocator (ANT). BaxBH3 but not Bcl2BH3 was found to interact with ANT, and only BaxBH3 (not Bcl2BH3) permeabilized ANT proteoliposomes and induced ANT to form non-specific channels in electrophysiological experiments. In contrast, both BaxBH3 and Bcl2BH3 were able to stimulate channel formation by recombinant Bax protein. Thus, BaxBH3 might induce MMP via an action on at least two targets, ANT and Bax-like proteins. In contrast, Bcl2BH3 would elicit MMP in an ANT-independent fashion. In purified mitochondria, two ligands of ANT, bongkrekic acid and the protein vMIA from cytomegalovirus, failed to prevent MMP induced by BaxBH3 or Bcl2BH3. In conclusion, BaxBH3 and Bcl2BH3 induce MMP and apoptosis through a mechanism which overcomes cytoprotection by Bcl-2 and Bcl-XL.