GAPDH as a sensor of NO stress

被引:168
作者
Hara, Makoto R.
Cascio, Matthew B.
Sawa, Akira
机构
[1] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA
[2] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21287 USA
[3] Johns Hopkins Univ, Sch Med, Grad Program Cellular & Mol Med, Baltimore, MD 21287 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2006年 / 1762卷 / 05期
关键词
GAPDH; nuclear translocation; oxidative stress; nitric oxide; Siah1; apoptosis;
D O I
10.1016/j.bbadis.2006.01.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classic glycolytic enzyme, and accumulating evidence has suggested that GAPDH is a multi-functional protein. In particular, its role as a mediator for cell death has been highlighted. For the last decade, many groups reported that a pool of GAPDH translocates to the nucleus under a variety of stressors, most of which are associated with oxidative stress. At the molecular level, sequential steps lead to nuclear translocation of GAPDH during cell death as follows: first, a catalytic cysteine in GAPDH (C150 in rat GAPDH) is S-nitrosylated by nitric oxide (NO) that is generated from inducible nitric oxide synthase (iNOS) and/or neuronal NOS (nNOS); second, the modified GAPDH becomes capable of binding with Siah1, an E3 ubiquitin ligase, and stabilizes it; third, the GAPDH-Siah protein complex translocates to the nucleus, dependent on Siah1's nuclear localization signal, and degrades Siah1's substrates in the nucleus, which results in cytotoxicity. A recent report suggests that GAPDH may be genetically associated with late-onset of Alzheimer's disease. (-)-deprenyl, which has originally been used as a monoamine oxidase inhibitor for Parkinson's disease, binds to GAPDH and displays neuroprotective actions, but its molecular mechanism is still unclear. The NO/GAPDH/ Siah1 death cascade will contribute to the molecular understanding of a role of GAPDH in neurodegenerative disorders and help to establish novel therapeutic strategies. (c) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:502 / 509
页数:8
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