MAPK and akt Act cooperatively but independently on hypoxia inducible factor-1α in rasV12 upregulation of VEGF

Akrit Sodhi, Silvia Montaner, Hiroshi Miyazaki, J. Silvio Gutkind

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

Oncogenic ras upregulates the expression of VEGF through the activation of the transcriptional enhancer hypoxia inducible factor-1α (HIF-1α) by a still poorly understood mechanism. Here, we demonstrate that both the Raf/MEK/MAPK and the PI3 kinase/Akt signaling pathways potently and additively stimulate the expression from a hypoxia response element (HRE) within the 5′flanking region of the VEGF promoter. Interestingly, while MAPK appears to specifically upregulate the transactivation activity of HIF-1α through direct phosphorylation of its regulatory/inhibitory domain, GSK-3, a downstream target of Akt, directly phosphorylates the HIF-1α oxygen-dependent degradation domain. These results suggest a novel mechanism whereby two divergent signaling pathways emerging from Ras may cooperatively but independently regulate the activity of a HIF-1α, thereby promoting the expression of a potent angiogenic mediator.

Original languageEnglish (US)
Article number95532
Pages (from-to)292-300
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume287
Issue number1
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Akt kinase
  • Hypoxia inducible factor-1
  • MAPK
  • Neovascularization
  • Ras
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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