TY - JOUR
T1 - GAPDH as a sensor of NO stress
AU - Hara, Makoto R.
AU - Cascio, Matthew B.
AU - Sawa, Akira
N1 - Funding Information:
We thank Ms. Yukiko Lema in preparation of figures and typing. We thank Dr. Solomon H. Snyder and Dr. Pamela Talalay for critical reading of the manuscript. This work was supported by USPHS grants MH-069853 (AS), foundation grants from NARSAD (AS), Stanley (AS), S-R (AS), and funds from the departments (AS).
PY - 2006/5
Y1 - 2006/5
N2 - 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.
AB - 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.
KW - Apoptosis
KW - GAPDH
KW - Nitric oxide
KW - Nuclear translocation
KW - Oxidative stress
KW - Siah1
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U2 - 10.1016/j.bbadis.2006.01.012
DO - 10.1016/j.bbadis.2006.01.012
M3 - Review article
C2 - 16574384
AN - SCOPUS:33646103670
SN - 0925-4439
VL - 1762
SP - 502
EP - 509
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 5
ER -