Nitric oxide as a bioregulator of apoptosis.
Nitric oxide (NO), synthesized from l-arginine by NO synthases, is a small, diffusible, highly reactive molecule with dichotomous regulatory roles under physiological and pathological conditions. NO can promote apoptosis (proapoptosis) in some cells, whereas it inhibits apoptosis (antiapoptosis) in other cells. This complexity is a consequence of the rate of NO production and the interaction with biological molecules such as iron, thiols, proteins, and reactive oxygen species. Long-lasting production of NO acts as a proapoptotic modulator by activating caspase family proteases through the release of mitochondrial cytochrome c into the cytosol, upregulation of p53 expression, activation of JNK/SAPK, and altering the expression of apoptosis-associated proteins including Bcl-2 family proteins. However, low or physiological concentrations of NO prevent cells from apoptosis induced by trophic factor withdrawal, Fas, TNFalpha, and lipopolysaccharide. The antiapoptotic mechanism can be understood via expression of protective genes such as heat shock proteins, Bcl-2 as well as direct inhibition of the apoptotic caspase family proteases by S-nitrosylation of the cysteine thiol. Our current understanding of the mechanisms by which NO exerts both pro- and antiapoptotic actions is discussed in this review article.
Chung
H T
HT
Department of Microbiology and Immunology, Wonkwang University, Chunbug, 570-749, Korea. htchung@wonnms.wonkwang.ac.kr
Pae
H O
HO
Choi
B M
BM
Billiar
T R
TR
Kim
Y M
YM
D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013438:Sulfhydryl Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D061945:Caspase Inhibitors; D002518:Ceramides; D003574:Cytochrome c Group; D006360:Heat-Shock Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases