Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death

被引:176
作者
Zhang, WH
Wang, X
Narayanan, M
Zhang, Y
Huo, CF
Reed, JC
Friedlander, RM
机构
[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg,Neuroapoptosis Lab, Boston, MA 02115 USA
[2] Burnham Inst, La Jolla, CA 92037 USA
关键词
D O I
10.1073/pnas.2534856100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Caspase-1 plays a key role in inflammatory pathways by processing pro-IL-1beta into the active cytokine mature IL-1beta. Given its sequence similarity with the Caenorhabditis elegans cell death gene ced-3, it has long been speculated that caspase-1 may also play a role in cell death. However, an unequivocal role for caspase-1 in cell death has been questioned, and not definitively demonstrated. Furthermore, if caspase-1 does play a role in cell death, its position in the apoptotic hierarchy has not been clearly defined. Previous studies have shown that caspase-1 knockout (KO) mice and transgenic mice expressing a dominant-negative caspase-1 construct are resistant to ischemic brain injury. We provide direct evidence that caspase-1 plays a key role in neuronal cell death and that caspase-1 is an apical activator of the cell death pathway in the premitochondrial collapse stage. Furthermore, we demonstrate that Rip2/Cardiak/Rick is a stress-inducible upstream modulator of procaspase-1 apoptotic activation. We provide evidence that Bid cleavage appears to be an important downstream effector of caspase-1-mediated cell death. Our data demonstrate that caspase-1 is an apical mediator of neuronal cell death during in vitro hypoxia, and confirmed in vivo in ischemia, and provide insights into the sequence of events involved in this pathological cell death process.
引用
收藏
页码:16012 / 16017
页数:6
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