著作: Aoki Hiroki/Kang M. Peter/Hampe James/Yoshimura Koichi/[野間 隆文]/Matsuzaki Masunori/Izumo Seigo/Direct activation of mitovhondrial apoptosis machinery by c-jun N-terminal kinase in adult cardiac myocytes/[The Journal of Biological Chemistry]
(英) Direct activation of mitovhondrial apoptosis machinery by c-jun N-terminal kinase in adult cardiac myocytes
(英) Although oxidative stress causes activation of c-Jun N-terminal kinase (JNK) and apoptosis in many cell types, how the JNK pathway is connected to the apoptosis pathway is unclear. The molecular mechanism of JNK-mediated apoptosis was investigated in adult rat cardiac myocytes in culture as a model system that is sensitive to oxidative stress. Oxidative stress caused JNK activation, cytochrome c release, and apoptosis without new protein synthesis. Oxidative stress-induced apoptosis was abrogated by dominant negative stress-activated protein kinase/extracellular signal-regulated kinase kinase-1 (SEK1)-mediated inhibition of the JNK pathway, whereas activation of the JNK pathway by constitutively active SEK1 was sufficient to cause apoptosis. Inhibition of caspase-9, an apical caspase in the mitochondrial apoptosis pathway, suppressed oxidative stress-induced apoptosis, whereas inhibition of caspase-8 had no effect, indicating that both the JNK pathway and the mitochondrial apoptosis machinery are central to oxidative stress-induced apoptosis. Both JNK and SEK1 localized on mitochondria where JNK was activated by oxidative stress. Furthermore, active JNK caused the release of apoptogenic factors such as cytochrome c from isolated mitochondria in a cell-free assay. These findings indicate that the JNK pathway is a direct activator of mitochondrial death machinery without other cellular components and provide a molecular linkage from oxidative stress to the mitochondrial apoptosis machinery.
|発行所||推奨||The American Society for Biochemistry and Molecular Biology|
The Journal of Biological Chemistry([The American Society for Biochemistry and Molecular Biology])
|年月日||必須||2002年 3月 22日|