Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 9, Pages 4748-4753Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.080072497
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Funding
- NHLBI NIH HHS [R01-HL55338, R01 HL055338, T32-HL07525, T32 HL007525] Funding Source: Medline
- NIDDK NIH HHS [R01-DK39869] Funding Source: Medline
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Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates cellular and systemic homeostatic responses to reduced O-2 availability in mammals, including angiogenesis. erythropoiesis, and glycolysis. HIF-1 activity is controlled by the O-2-regulated expression of the HIF-1 alpha subunit, Under nonhypoxic conditions, HIF-1 alpha protein is subject to ubiquitination and proteasomal degradation. Here we report that missense mutations and/or deletions involving several different regions of HIF-1 alpha result in constitutive expression and transcriptional activity in nonhypoxic cells. We demonstrate that hypoxia results in decreased ubiquitination of HIF-1 alpha and that missense mutations increase HIF-1 alpha expression under nonhypoxic conditions by blocking ubiquitination.
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