Ras-dependent induction of HIF-1alpha785 via the Raf/MEK/ERK pathway: a novel mechanism of Ras-mediated tumor promotion.
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.
Lim
Ji-Hong
JH
Human Genome Research Institute and Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
Lee
Eun-Seo
ES
You
Ho-Jin
HJ
Lee
Jung Weon
JW
Park
Jong-Wan
JW
Chun
Yang-Sook
YS
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate