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Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor

Academic Article
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Overview

authors

  • Jiang, B. H.
  • Jiang, G.
  • Zheng, J. Z.
  • Lu, Z.
  • Hunter, T.
  • Vogt, Peter K.

publication date

  • July 2001

journal

  • Cell Growth & Differentiation  Journal

abstract

  • 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.

subject areas

  • Androstadienes
  • Blotting, Northern
  • Cell Fractionation
  • Chromones
  • Culture Media, Serum-Free
  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Epidermal Growth Factor
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoblotting
  • Insulin
  • Lymphokines
  • Morpholines
  • Nuclear Proteins
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases
  • Phosphoric Monoester Hydrolases
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Transcription Factors
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
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Identity

International Standard Serial Number (ISSN)

  • 1044-9523

PubMed ID

  • 11457733
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Additional Document Info

start page

  • 363

end page

  • 369

volume

  • 12

issue

  • 7

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