Two transactivation domains of hypoxia-inducible factor-1α regulated by the MEK-1/p42/p44 MARK pathway

Eunjung Lee, Sujin Yim, Seung Ki Lee, Hyunsung Park

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

At a low-oxygen tension, cells increase the expression of several genes (such as erythropoietin, the vascular endothelial growth factor, and glycolytic enzymes) in order to adapt to hypoxic stress. A common transactivator, named the hypoxia-inducible factor 1 (HIF-1) activates these genes. HIF-I is a heterodimeric transactivator that is composed of α and β subunits. HIF-1 activity is primarily determined by the hypoxia-induced stabilization of the α subunit, whereas the HIF-1β subunit is expressed constitutively. Our previous observation implied that the MEK-I/p42/p44 MAPK pathway is involved in the hypoxia-induced transactivation ability, but not in the stabilization and DNA binding of HIF-1α. In this paper, we dissected the transactivation domain of HIF-1α in more detail, and tested the correlation between specific domains of HIF-1α and specific signaling pathways. We designed several fusion proteins that contain deletion mutants of HIF-1α that is linked to the DNA binding domain of the yeast protein Gal4. By using the Gal4-driven reporter system, we tested the transactivation activities of the Gal4/HIF-1α fusion proteins in Hep3B cells. Our findings suggest that tyrosine kinases, the MEK-1/p42/p44 MAPK pathway, but not the PI-3 kinase/ Akt pathway, are involved in the hypoxia-induced transactivation of HIF-1α. We have shown that the functional transactivation activities are located at both 522-649 and 650-822 amino acids of HIF-1α. Treatment of PD98059, a MEK-1 inhibitor, blocked the hypoxia-induced transactivation abilities of both the 522 -649 and 650-822 amino acids of the C- terminal half of HIF-1α. This implies that the MEK-1/ p42/p44 MAPK signaling pathway cannot distinguish between the two hypoxia-induced transactivation domains.

Original languageEnglish
Pages (from-to)9-15
Number of pages7
JournalMolecules and Cells
Volume14
Issue number1
StatePublished - Aug 2002

Keywords

  • Hypoxia-inducible Factor 1α
  • MEK-1/p42/p44 MAPK
  • Transactivation

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