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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Numayama-tsuruta, K. Sogawa, K. Abe, M. Fujii-kuriyama, Y. Abe, H. Ema, M. |
| Description | Author Affiliation: Sogawa K ( Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-77, Japan. sogawa@mail.cc.tohoku.ac.jp); |
| Abstract | Nitric oxide (NO) is known to have various biologic and pathophysiologic effects on organisms. The molecular mechanisms by which NO exerts harmful effects are unknown, although various O2 radicals and ions that result from reactivity of NO are presumed to be involved. Here we report that adaptive cellular response controlled by the transcription factor hypoxia-inducible factor 1 (HIF-1) in hypoxia is suppressed by NO. Induction of erythropoietin and glycolytic aldolase A mRNAs in hypoxically cultured Hep3B cells, a human hepatoma cell line, was completely and partially inhibited, respectively, by the addition of sodium nitroprusside (SNP), which spontaneously releases NO. A reporter plasmid carrying four hypoxia-response element sequences connected to the luciferase structural gene was constructed and transfected into Hep3B cells. Inducibly expressed luciferase activity in hypoxia was inhibited by the addition of SNP and two other structurally different NO donors, S-nitroso-L-glutathione and 3-morpholinosydnonimine, giving IC50 values of 7.8, 211, and 490 microM, respectively. Inhibition by SNP was also observed in Neuro 2A and HeLa cells, indicating that the inhibition was not cell-type-specific. The vascular endothelial growth factor promoter activity that is controlled by HIF-1 was also inhibited by SNP (IC50 = 6.6 microM). Induction generated by the addition of cobalt ion (this treatment mimics hypoxia) was also inhibited by SNP (IC50 = 2.5 microM). Increased luciferase activity expressed by cotransfection of effector plasmids for HIF-1alpha or HIF-1alpha-like factor in hypoxia was also inhibited by the NO donor. We also showed that the inhibition was performed by blocking an activation step of HIF-1alpha to a DNA-binding form. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 13 |
| Volume Number | 95 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 1998-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | DNA-Binding Proteins Antagonists & Inhibitors Helix-Loop-Helix Motifs Nitric Oxide Metabolism Nuclear Proteins Transcription Factors Transcription, Genetic Cell Hypoxia Cells, Cultured DNA Drug Effects Enzyme Induction Erythropoietin Biosynthesis Genetics Fructose-Bisphosphate Aldolase Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, Alpha Subunit Nitroprusside Pharmacology RNA, Messenger Transfection Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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