Document Detail


Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1.
MedLine Citation:
PMID:  11457733     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
B H Jiang; G Jiang; J Z Zheng; Z Lu; T Hunter; P K Vogt
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research     Volume:  12     ISSN:  1044-9523     ISO Abbreviation:  Cell Growth Differ.     Publication Date:  2001 Jul 
Date Detail:
Created Date:  2001-07-17     Completed Date:  2001-10-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9100024     Medline TA:  Cell Growth Differ     Country:  United States    
Other Details:
Languages:  eng     Pagination:  363-9     Citation Subset:  IM    
Affiliation:
Department of Molecular and Experimental Medicine, BCC239, The Scripps Research Institute, La Jolla, California 92037, USA.
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MeSH Terms
Descriptor/Qualifier:
1-Phosphatidylinositol 3-Kinase / antagonists & inhibitors,  metabolism*
Androstadienes / pharmacology
Blotting, Northern
Cell Fractionation
Chromones / pharmacology
Culture Media, Serum-Free
DNA-Binding Proteins / metabolism*
Endothelial Growth Factors / metabolism
Enzyme Inhibitors / pharmacology
Epidermal Growth Factor / metabolism
Gene Expression Regulation / drug effects
Genes, Reporter
Humans
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Immunoblotting
Insulin / pharmacology
Lymphokines / metabolism
Morpholines / pharmacology
Nuclear Proteins / metabolism*
PTEN Phosphohydrolase
Phosphoric Monoester Hydrolases / genetics,  metabolism
Recombinant Fusion Proteins / genetics,  metabolism
Signal Transduction / physiology*
Transcription Factors*
Tumor Cells, Cultured
Tumor Suppressor Proteins*
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Grant Support
ID/Acronym/Agency:
CA 42564/CA/NCI NIH HHS; CA 78230/CA/NCI NIH HHS; CA14195/CA/NCI NIH HHS; CA82863/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Androstadienes; 0/Chromones; 0/Culture Media, Serum-Free; 0/DNA-Binding Proteins; 0/Endothelial Growth Factors; 0/Enzyme Inhibitors; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Lymphokines; 0/Morpholines; 0/Nuclear Proteins; 0/Recombinant Fusion Proteins; 0/Transcription Factors; 0/Tumor Suppressor Proteins; 0/Vascular Endothelial Growth Factor A; 0/Vascular Endothelial Growth Factors; 11061-68-0/Insulin; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 19545-26-7/wortmannin; 62229-50-9/Epidermal Growth Factor; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase

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