Journal
CANCER AND METASTASIS REVIEWS
Volume 19, Issue 1-2, Pages 59-65Publisher
KLUWER ACADEMIC PUBL
DOI: 10.1023/A:1026544214667
Keywords
AKT; MAP kinase; p53; phosphatidylinositol-3-kinase; PTEN; SRC; vascular endothelial growth factor; von Hippel-Lindau protein
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Funding
- NHLBI NIH HHS [R01-HL55338] Funding Source: Medline
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In brain, breast, and other common human tumors there is a correlation between expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and tumor grade and vascularization. HIF-1 stimulates angiogenesis by activating transcription of the gene encoding vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer consisting of a constitutively-expressed HIF-1 beta subunit and an O-2- and growth factor-regulated HIF-1 alpha subunit. Recent studies have demonstrated that HIF-1 alpha expression is increased in tumor relative to normal tissue by two mechanisms. First, decreased intratumoral O-2 concentrations provide a physiological stimulus. Second, genetic alterations that activate oncogene products or inactivate tumor suppressor gene products increase HIF-1 alpha expression and/or HIF-1 transcriptional activity independent of the O-2 concentration. Taken together, these recent data suggest that increased HIF-1 activity provides a molecular basis for VEGF-induced angiogenesis and other adaptations of cancer cells to hypoxia that are critical for establishment of a primary tumor and its progression to the lethal phenotype.
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