Nitric oxide as a pro-apoptotic as well as anti-apoptotic modulator.
Nitric oxide (NO), synthesized from L-arginine by NO synthases, is a small, lipophilic, diffusible, highly reactive molecule with dichotomous regulatory roles in many biological events under physiological and pathological conditions. NO can promote apoptosis (pro-apoptosis) in some cells, whereas it inhibits apoptosis (anti-apoptosis) in other cells. This complexity is a consequence of the rate of NO production and the interaction with biological molecules such as metal ion, thiol, protein tyrosine, and reactive oxygen species. Long-lasting overproduction of NO acts as a pro-apoptotic modulator, activating caspase family proteases through the release of mitochondrial cytochrome c into cytosol, up-regulation of the p53 expression, and alterations in the expression of apoptosis-associated proteins, including the Bcl-2 family. However, low or physiological concentrations of NO prevent cells from apoptosis that is induced by the trophic factor withdrawal, Fas, TNFalpha/ActD, and LPS. The anti-apoptotic mechanism is understood on the basis of gene transcription of protective proteins. These include: heat shock protein, hemeoxygenase, or cyclooxygenase-2 and direct inhibition of the apoptotic executive effectors caspase family protease by S-nitrosylation of the cysteine thiol group in their catalytic site in a cell specific way. Our current understanding of the mechanisms by which NO exerts both pro- and anti-apototic action is discussed in this review article.
Choi
Byung-Min
BM
Medicinal Resources Research Center (MRRC), Wonkwang University, Iksan, Chunbug, Korea.
Pae
Hyun-Ock
HO
Jang
Seon Il
SI
Kim
Young-Myeong
YM
Chung
Hun-Taeg
HT
D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000737:chemistry; D020169:Caspases / Q000378:metabolism; D020134:Catalytic Domain; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002518:Ceramides; D008070:Lipopolysaccharides; D013438:Sulfhydryl Compounds; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D045304:Cytochromes c; D001120:Arginine; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D003545:Cysteine