Han Jie, Goldstein Leslie A, Hou Wen, Rabinowich Hannah
Department of Pathology, University of Pittsburgh School of Medicine, PA 15213, USA.
J Biol Chem. 2007 Jun 1;282(22):16223-31. doi: 10.1074/jbc.M611186200. Epub 2007 Mar 20.
NOXA is a BH3-only protein whose expression is induced by certain p53-depenent or independent apoptotic stimuli. Both NOXA and Bim are avid binders of Mcl-1, but a functional linkage between these BH3-only proteins has not yet been reported. In this study, we demonstrate that Mcl-1 binding of endogenously induced NOXA interferes with the ability of Mcl-1 to efficiently sequester endogenous Bim, as Bim is displaced from its complex with Mcl-1. Induced NOXA significantly enhances the UV sensitivity of cells, and the ensuing mitochondrial depolarization is entirely abrogated by Bim knockdown. These results demonstrate a Mcl-1-mediated cross-talk between endogenous NOXA and Bim that occurs upstream of the Bak/Bax-dependent execution of UV-induced mitochondrial depolarization. The current findings demonstrate that the mitochondrial response to an induced expression of NOXA is executed by endogenous Bim and suggest a plausible mechanism for the observed NOXA-Bim linkage.
NOXA是一种仅含BH3结构域的蛋白，其表达由某些p53依赖或非依赖的凋亡刺激所诱导。NOXA和Bim都是Mcl-1的强力结合蛋白，但尚未有关于这些仅含BH3结构域蛋白之间功能联系的报道。在本研究中，我们证明内源性诱导的NOXA与Mcl-1的结合会干扰Mcl-1有效隔离内源性Bim的能力，因为Bim会从其与Mcl-1的复合物中被置换出来。诱导产生的NOXA显著增强细胞对紫外线的敏感性，而随后发生的线粒体去极化会被Bim基因敲低完全消除。这些结果表明，内源性NOXA和Bim之间存在一种由Mcl-1介导的相互作用，这种相互作用发生在Bak/Bax依赖的紫外线诱导的线粒体去极化执行的上游。目前的研究结果表明，线粒体对诱导表达的NOXA的反应是由内源性Bim执行的，并为观察到的NOXA-Bim联系提出了一种合理的机制。
