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dc.contributor.authorCarroll, VA
dc.contributor.authorAshcroft, M
dc.identifier.citationCANCER RESEARCH, 2006, 66 pp. 6264 - 6270
dc.description.abstractOverexpression of hypoxia-inducible factors (HIF), HIF-1 alpha and HIF-2 alpha, leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism and is associated with tumor progression in several cancers. However, the contribution of HIF-1 alpha versus HIF-2 alpha to vascular endothelial growth factor (VEGF) expression and other HIF-regulated target genes under different conditions is unclear. To address this, we used small interfering RNA (siRNA) techniques to knockdown HIF-1 alpha and/or HIF-2 alpha expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1 alpha and/or HIF-2 alpha due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1 alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2 alpha in MCF-7 cells. We also observed a reciprocal relationship between HIF-1 alpha and HIF-2a expression in hypoxia in these cells: HIF-2 alpha siRNA enhanced HIF-1 alpha-mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1 alpha siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1 alpha and HIF-2 alpha due to loss of VHL function, we found that high basal VEGF, glucose transporter-1, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 expression was predominantly dependent on HIF-2 alpha. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2 alpha protein expression and HIF-2 alpha-regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically.
dc.format.extent6264 - 6270
dc.titleRole of hypoxia-inducible factor (HIF)-1 alpha-versus HIF-2 alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-1, or loss of von Hippel-Lindau function: Implications for targeting the HIF pathway
dc.typeJournal Article
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCANCER RESEARCH
pubs.notesaffiliation: Ashcroft, M (Reprint Author), Inst Canc Res, Canc Res UK, Ctr Canc Therapeut, Cell Growth Regulat & Angiogenesis Lab, Sutton SM2 5NG, Surrey, England. Inst Canc Res, Canc Res UK, Ctr Canc Therapeut, Cell Growth Regulat & Angiogenesis Lab, Sutton SM2 5NG, Surrey, England. keywords-plus: OSTEOBLAST-LIKE CELLS; COLON-CANCER CELLS; TOPOISOMERASE-I; EXPRESSION; FACTOR-1-ALPHA; INDUCTION; FACTOR-2-ALPHA; TRANSCRIPTION; HYPOXIA-INDUCIBLE-FACTOR-1-ALPHA; HIF-1-ALPHA research-areas: Oncology web-of-science-categories: Oncology author-email: [email protected] number-of-cited-references: 35 times-cited: 232 usage-count-last-180-days: 0 usage-count-since-2013: 22 journal-iso: Cancer Res. doc-delivery-number: 054LX unique-id: ISI:000238379500039 oa: gold_or_bronze da: 2018-09-03
pubs.notesNot known
pubs.embargo.termsNot known
dc.contributor.icrauthorAshcroft, Margareten

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