Ras-dependent induction of HIF-1alpha785 via the Raf/MEK/ERK pathway: a novel mechanism of Ras-mediated tumor promotion

Oncogene. 2004 Dec 16;23(58):9427-31. doi: 10.1038/sj.onc.1208003.


Hypoxia-inducible factor-1alpha (HIF-1alpha) plays crucial roles in tumor promotion by transactivating approximately 60 kinds of its target genes. Recently, we reported a novel splice variant HIF-1alpha(785), which is regulated primarily by phorbol ester. This variant can be stabilized under normoxic conditions because it loses an acetylation site Lys532. Its expression was found to promote xenografted tumor growth in nude mice. We here found that the Ras oncogene regulates HIF-1alpha(785) expression via the Raf/MEK/ERK pathway, and that both phorbol ester and epidermal growth factor also induced HIF-1alpha(785) via the same pathway. We also identified the nonhypoxic regulatory domain responsible for phorbol ester-induced HIF-1alpha(785) expression. These results imply that HIF-1alpha(785) may play an important role in tumor promotion mediated by the Ras oncogene, phorbol ester or tumor growth factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / biosynthesis*
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Genes, ras
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Nuclear Proteins / biosynthesis*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors / biosynthesis*


  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors
  • Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate