Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1.
Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1.
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发表时间：
2001-07
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通讯作者：
B. Jiang;Guoqiang Jiang;Jenny Z. Zheng;Zhimin Lu;T. Hunter;P. Vogt
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作者：
B. Jiang;Guoqiang Jiang;Jenny Z. Zheng;Zhimin Lu;T. Hunter;P. Vogt
磷脂酰肌醇3-激酶（PI 3 K）信号通路具有固有的致癌潜力。它在多种人类癌症中通过PI 3 K本身或其下游靶Akt的功能获得或通过负调节因子PTEN的功能丧失而上调。然而，这种上调的完整后果尚不清楚。在这里，我们表明，胰岛素和表皮生长因子或失活突变的肿瘤抑制基因PTEN特异性地增加蛋白水平的缺氧诱导因子（HIF）1 α，但不是HIF-1 β在人类癌细胞系。HIF-1 α蛋白表达的这种特异性升高需要PI 3 K信号。在前列腺癌衍生细胞系PC-3和DU 145中，胰岛素和表皮生长因子诱导的HIF-1 α表达被PI 3 K特异性抑制剂LY 294002和渥曼青霉素以剂量依赖性方式抑制。HIF-1 β表达不受这些抑制剂的影响。将野生型PTEN导入PTEN阴性的PC-3细胞系，特异性抑制HIF-1 α的表达，但不抑制HIF-1 β的表达。与HIF-1 α蛋白相反，HIF-1 α mRNA水平不受PI 3 K信号的显著影响。血管内皮生长因子报告基因活性在PC-3细胞中由胰岛素诱导，并由PI 3 K抑制剂LY 294002和HIF-1显性负性构建体的共表达抑制。血管内皮生长因子报告基因活性也被抑制的显性负PI 3 K结构的表达和肿瘤抑制基因PTEN。
The phosphatidylinositol 3-kinase (PI3K) signaling pathway has inherent oncogenic potential. It is up-regulated in diverse human cancers by either a gain of function in PI3K itself or in its downstream target Akt or by a loss of function in the negative regulator PTEN. However, the complete consequences of this up-regulation are not known. Here we show that insulin and epidermal growth factor or an inactivating mutation in the tumor suppressor PTEN specifically increase the protein levels of hypoxia-inducible factor (HIF) 1alpha but not of HIF-1beta in human cancer cell lines. This specific elevation of HIF-1alpha protein expression requires PI3K signaling. In the prostate carcinoma-derived cell lines PC-3 and DU145, insulin- and epidermal growth factor-induced expression of HIF-1alpha was inhibited by the PI3K-specific inhibitors LY294002 and wortmannin in a dose-dependent manner. HIF-1beta expression was not affected by these inhibitors. Introduction of wild-type PTEN into the PTEN-negative PC-3 cell line specifically inhibited the expression of HIF-1alpha but not that of HIF-1beta. In contrast to the HIF-1alpha protein, the level of HIF-1alpha mRNA was not significantly affected by PI3K signaling. Vascular endothelial growth factor reporter gene activity was induced by insulin in PC-3 cells and was inhibited by the PI3K inhibitor LY294002 and by the coexpression of a HIF-1 dominant negative construct. Vascular endothelial growth factor reporter gene activity was also inhibited by expression of a dominant negative PI3K construct and by the tumor suppressor PTEN.