由死亡信号引发的线粒体决定细胞对抗凋亡BCL-2家族成员的依赖性。

Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members.

作者信息

Certo Michael, Del Gaizo Moore Victoria, Nishino Mari, Wei Guo, Korsmeyer Stanley, Armstrong Scott A, Letai Anthony

机构信息

Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.

出版信息

Cancer Cell. 2006 May;9(5):351-65. doi: 10.1016/j.ccr.2006.03.027.

DOI:10.1016/j.ccr.2006.03.027

PMID:16697956

Abstract

We show that the antiapoptotic proteins BCL-2, BCL-XL, MCL-1, BFL-1, and BCL-w each bear a unique pattern of interaction with a panel of peptides derived from BH3 domains of BH3-only proteins. Cellular dependence on an antiapoptotic protein for survival can be decoded based on the pattern of mitochondrial sensitivity to this peptide panel, a strategy that we call BH3 profiling. Dependence on antiapoptotic proteins correlates with sequestration of activator BH3-only proteins like BID or BIM by antiapoptotic proteins. Sensitivity to the cell-permeable BCL-2 antagonist ABT-737 is also related to priming of BCL-2 by activator BH3-only molecules. Our data allow us to distinguish a cellular state we call "primed for death," which can be determined by BH3 profiling and which correlates with dependence on antiapoptotic family members for survival.

摘要

我们发现抗凋亡蛋白BCL-2、BCL-XL、MCL-1、BFL-1和BCL-w各自与一组源自仅含BH3结构域蛋白的BH3结构域的肽段呈现独特的相互作用模式。细胞对某种抗凋亡蛋白的生存依赖性可根据线粒体对该肽段组的敏感性模式来解读，我们将此策略称为BH3分析。对抗凋亡蛋白的依赖性与抗凋亡蛋白对激活剂类仅含BH3结构域蛋白（如BID或BIM）的隔离有关。对细胞可渗透的BCL-2拮抗剂ABT-737的敏感性也与激活剂类仅含BH3结构域分子对BCL-2的启动作用有关。我们的数据使我们能够区分一种我们称为“死亡致敏”的细胞状态，这种状态可通过BH3分析来确定，并且与生存对抗凋亡家族成员的依赖性相关。