Insulin and hypoxia share common target genes but not the hypoxia-inducible factor-1α

Sujin Yim, Su Mi Choi, Youngyeon Choi, Naery Lee, Jieun Chung, Hyunsung Park

Research output: Contribution to journalArticlepeer-review

Abstract

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-1α and the aromatic hydrocarbon nuclear translocator (Arnt). Hypoxia-induced gene expression is initiated by the stabilization of the HIF-1α subunit. Here we investigated whether insulin-induced gene expression also requires stabilization of HIF-1α. Our results indicate that hypoxia but not insulin stabilizes HIF-1α 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-1α, which triggers recruitment of the von Hippel-Lindau protein and oxygen-dependent degradation of HIF-1α. 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-1α protein. We believe that insulin activates other putative partner proteins for Arnt in PI 3-kinase- and H2O 2-dependent pathways.

Original languageEnglish (US)
Pages (from-to)38260-38268
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number40
DOIs
StatePublished - Oct 3 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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