Nitric oxide induces hypoxia-inducible factor 1 activation that is dependent on MAPK and phosphatidylinositol 3-kinase signaling
Nitric oxide induces hypoxia-inducible factor 1 activation that is dependent on MAPK and phosphatidylinositol 3-kinase signaling
复制标题
DOI：
10.1074/jbc.m308197200
复制
发表时间：
2004-01-23
影响因子：
4.8
通讯作者：
Hirota, K
中科院分区：
文献类型：
--
作者：
Kasuno, K;Takabuchi, S;Hirota, K
缺氧诱导因子-1（HIF-1）是细胞缺氧适应性反应的主要调节因子。HIF-1 α亚单位的水平在缺氧条件下增加。在非缺氧条件下，细胞暴露于某些一氧化氮（NO）供体也诱导HIF-1 α表达。我们证明，暴露于NO供体NOC 18或S-亚硝基谷胱甘肽细胞诱导HIF-1 α表达和转录活性。与缺氧相反，NOC 18不抑制HIF-1 α羟基化、泛素化和降解，表明脉冲标记研究证实了对HIF-1 α蛋白合成的影响。用磷脂酰肌醇3-激酶或MAPK信号通路抑制剂处理细胞，可阻断NOC 18对HIF-1 α蛋白和HIF-1依赖性基因表达的刺激。这些抑制剂还阻断了NOC 18诱导的翻译调节蛋白4 E-BP 1、p70 S6激酶和eIF-4 E的磷酸化，从而提供了调节HIF-1 α蛋白合成的机制。此外，显性负性形式的Ras的表达显著抑制了NOC 18对HIF-1的激活。我们的结论是，NO供体NOC 18诱导HIF-1 α的合成条件下，NO形成过程中常氧和HIF-1 α的羟基化不受NOC 18。
Hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular adaptive responses to hypoxia. Levels of the HIF-1alpha subunit increase under hypoxic conditions. Exposure of cells to certain nitric oxide (NO) donors also induces HIF-1alpha expression under nonhypoxic conditions. We demonstrate that exposure of cells to the NO donor NOC18 or S-nitrosoglutathione induces HIF-1alpha expression and transcriptional activity. In contrast to hypoxia, NOC18 did not inhibit HIF-1alpha hydroxylation, ubiquitination, and degradation, indicating an effect on HIF-1alpha protein synthesis that was confirmed by pulse labeling studies. NOC18 stimulation of HIF-1alpha protein and HIF-1-dependent gene expression was blocked by treating cells with an inhibitor of the phosphatidylinositol 3-kinase or MAPK-signaling pathway. These inhibitors also blocked NOC18-induced phosphorylation of the translational regulatory proteins 4E-BP1, p70 S6 kinase, and eIF-4E, thus providing a mechanism for the modulation of HIF-1alpha protein synthesis. In addition, expression of a dominant-negative form of Ras significantly suppressed HIF-1 activation by NOC18. We conclude that the NO donor NOC18 induces HIF-1alpha synthesis under conditions of NO formation during normoxia and that hydroxylation of HIF-1alpha is not regulated by NOC18.