Hypoxia-inducible factors, hypoxia, and tumor angiogenesis.
OBJECTIVE
The transcription factor hypoxia-inducible factor is activated by low oxygen to promote the expression of target genes that allow cellular, tissue, and organismal adaptation to low oxygen. Hypoxia-inducible factor is activated not only by hypoxia but also as a consequence of genetic mutations in a variety of tumors. This review summarizes recent studies on hypoxia-inducible factor-alpha functions in development and tumorigenesis.


RESULTS
Deficiency of the tumor suppressor von Hippel-Lindau leads to constitutively active hypoxia-inducible factor and hypoxia-inducible factor target gene expression. Other genetic lesions, however, e.g. in JunD, can also result in elevated hypoxia-inducible factor levels. The specific functions of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha during development and tumor growth remain incompletely understood. Whereas hypoxia-inducible factor-2alpha seems to be the critical hypoxia factor in renal cell carcinoma, hypoxia-inducible factor-1alpha plays a significant role in the growth of tumors in other tissues. Loss of von Hippel-Lindau is not sufficient for neoplastic transformation, suggesting that hypoxia-inducible factor does not act alone to cause tumors.


CONCLUSIONS
It will be important to further characterize the specific roles of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha during tumorigenesis to design therapies targeting the relevant isoform for specific diseases. It is also necessary to investigate the effect of reducing hypoxia-inducible factor levels on other angiogenic factors.
Gruber
Michaela
M
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Simon
M Celeste
MC
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1