PMID- 12876287
OWN - NLM
STAT- MEDLINE
DCOM- 20031106
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 40
DP  - 2003 Oct 3
TI  - Insulin and hypoxia share common target genes but not the hypoxia-inducible 
      factor-1alpha.
PG  - 38260-8
AB  - Both hypoxia and insulin induce common target genes, including vascular 
      endothelial growth factors and several glycolytic enzymes. However, these two 
      signals eventually trigger quite different metabolic pathways. Hypoxia induces 
      glycolysis, resulting in anaerobic ATP production, while insulin increases 
      glycolysis for energy storage. Hypoxia-induced gene expression is mediated by the 
      hypoxia-inducible factor-1 (HIF-1) that consists of HIF-1alpha and the aromatic 
      hydrocarbon nuclear translocator (Arnt). Hypoxia-induced gene expression is 
      initiated by the stabilization of the HIF-1alpha subunit. Here we investigated 
      whether insulin-induced gene expression also requires stabilization of 
      HIF-1alpha. Our results indicate that hypoxia but not insulin stabilizes 
      HIF-1alpha protein levels, whereas both insulin- and hypoxia-induced gene 
      expression require the presence of the Arnt protein. Insulin treatment fails to 
      inactivate proline hydroxylation of HIF-1alpha, which triggers recruitment of the 
      von Hippel-Lindau protein and oxygen-dependent degradation of HIF-1alpha. 
      Insulin-induced gene expression is inhibited by the presence of the 
      phosphoinositide (PI) 3-kinase inhibitor LY294002 and the dominant negative 
      mutant of the p85 subunit of PI 3-kinase, whereas hypoxia-induced gene expression 
      is not. Pyrrolidine dithiocarbamate, a scavenger of H2O2, reduces insulin-induced 
      gene expression but not hypoxia-induced gene expression. Although both hypoxia 
      and insulin induce the expression of common target genes through a 
      hypoxia-responsive element- and Arnt-dependent mechanism, insulin cannot 
      stabilize the HIF-1alpha protein. We believe that insulin activates other 
      putative partner proteins for Arnt in PI 3-kinase- and H2O2-dependent pathways.
FAU - Yim, Sujin
AU  - Yim S
AD  - Department of Life Science, University of Seoul, Seoul 130-743, Korea.
FAU - Choi, Su Mi
AU  - Choi SM
FAU - Choi, Youngyeon
AU  - Choi Y
FAU - Lee, Naery
AU  - Lee N
FAU - Chung, Jieun
AU  - Chung J
FAU - Park, Hyunsung
AU  - Park H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030721
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (ARNT protein, human)
RN  - 0 (Arnt protein, mouse)
RN  - 0 (Chromones)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Insulin)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Pyrrolidines)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Thiocarbamates)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator)
RN  - 25769-03-3 (pyrrolidine dithiocarbamic acid)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 3G0H8C9362 (Cobalt)
RN  - 63231-63-0 (RNA)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 2.5.1.18 (Glutathione Transferase)
RN  - EC 6.- (Ligases)
RN  - EC 6.3.2.- (VHL protein, human)
RN  - EVS87XF13W (cobaltous chloride)
SB  - IM
MH  - 3T3 Cells
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Aryl Hydrocarbon Receptor Nuclear Translocator
MH  - Base Sequence
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - Cell Line
MH  - Cell Nucleus/metabolism
MH  - Chromones/pharmacology
MH  - Cobalt/pharmacology
MH  - *DNA-Binding Proteins
MH  - Dimerization
MH  - Dose-Response Relationship, Drug
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Genes, Dominant
MH  - Glutathione Transferase/metabolism
MH  - Glycolysis
MH  - HeLa Cells
MH  - Humans
MH  - Hydrogen Peroxide/pharmacology
MH  - *Hypoxia
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Insulin/*metabolism/pharmacology
MH  - Ligases/metabolism
MH  - Luciferases/metabolism
MH  - Mice
MH  - Molecular Sequence Data
MH  - Morpholines/pharmacology
MH  - Mutation
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Plasmids/metabolism
MH  - Pyrrolidines/pharmacology
MH  - RNA/metabolism
MH  - *Receptors, Aryl Hydrocarbon
MH  - Thiocarbamates/pharmacology
MH  - Time Factors
MH  - Transcription Factors/*metabolism
MH  - Transfection
MH  - *Tumor Suppressor Proteins
MH  - *Ubiquitin-Protein Ligases
MH  - Von Hippel-Lindau Tumor Suppressor Protein
EDAT- 2003/07/24 05:00
MHDA- 2003/11/07 05:00
CRDT- 2003/07/24 05:00
PHST- 2003/07/24 05:00 [pubmed]
PHST- 2003/11/07 05:00 [medline]
PHST- 2003/07/24 05:00 [entrez]
AID - S0021-9258(20)83127-5 [pii]
AID - 10.1074/jbc.M306016200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Oct 3;278(40):38260-8. doi: 10.1074/jbc.M306016200. Epub 2003 
      Jul 21.