Nitric oxide affects the production of reactive oxygen species in hepatoma cells: implications for the process of oxygen sensing.
Treatment of human hepatoma cells (HepG2) with NO-donors for 24 h inhibited hypoxia-induced erythropoietin (EPO) gene activation. NO was found to increase the production of reactive oxygen species (ROS), the putative signaling molecules between a cellular O2-sensor and hypoxia inducible factor 1 (HIF-1). HIF-1 is the prime regulator of O2-dependent genes such as EPO. NO-treatment for more than 20 h reduced HIF-1-driven reporter gene activity. In contrast, immediately after the addition of NO, ROS levels in HepG2 cells decreased below control values for as long as 4 h. Corresponding to these lowered ROS-levels, HIF-1 reporter gene activity and EPO gene expression transiently increased but were reduced when ROS levels rose thereafter. Our findings of a bimodal effect of NO on ROS production shed new light on the involvement of ROS in the mechanism of O2-sensing and may explain earlier conflicting data about the effect of NO on O2-dependent gene expression.
Genius
J
J
Institute für Physiologie, Medizinische Universität zu Lübeck, Lübeck, Germany.
Fandrey
J
J
D000166:Acridines / Q000378:metabolism; D000693:Anaerobiosis; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D004921:Erythropoietin / Q000032:analysis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides; D009687:Nuclear Proteins / Q000235:genetics; D009861:Onium Compounds / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D000166:Acridines; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D009687:Nuclear Proteins; D009861:Onium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C110881:S-nitro-N-acetylpenicillamine; D014157:Transcription Factors; D004921:Erythropoietin; C091861:spermine nitric oxide complex; C033472:10,10'-dimethyl-9,9'-biacridinium; D013096:Spermine; D009569:Nitric Oxide; C007517:diphenyleneiodonium; D006861:Hydrogen Peroxide; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D010396:Penicillamine; D010100:Oxygen