Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1
| Autor: | Bh, Jiang, Jiang G, Jz, Zheng, Lu Z, Hunter T, Peter K Vogt |
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| Předmět: |
Vascular Endothelial Growth Factor A
Morpholines Recombinant Fusion Proteins Immunoblotting Endothelial Growth Factors Cell Fractionation Culture Media Serum-Free Phosphatidylinositol 3-Kinases Genes Reporter Tumor Cells Cultured Humans Insulin Enzyme Inhibitors Phosphoinositide-3 Kinase Inhibitors Lymphokines Epidermal Growth Factor Vascular Endothelial Growth Factors Tumor Suppressor Proteins PTEN Phosphohydrolase Nuclear Proteins Blotting Northern Hypoxia-Inducible Factor 1 alpha Subunit Phosphoric Monoester Hydrolases Androstadienes DNA-Binding Proteins Gene Expression Regulation Chromones Hypoxia-Inducible Factor 1 Wortmannin Signal Transduction Transcription Factors |
| Zdroj: | Europe PubMed Central |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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