Hypoxia-Inducible Factor 1 α Protein Expression Is Controlled by Oxygen-Regulated Ubiquitination That Is Disrupted by Deletions and Missense Mutations

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 9; pp. 4748 - 4753
• Main Authors: Sutter, Carrie Hayes, Laughner, Erik, Semenza, Gregg L.
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences of the United States of America 25.04.2000; National Acad Sciences; The National Academy of Sciences
• Subjects: Biological Sciences; Cell nucleus; COS cells; Gene expression regulation; Genetic mutation; Hypoxia; Missense mutation; Physiological regulation; Polymerase chain reaction; Protein synthesis; Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.080072497

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates cellular and systemic homeostatic responses to reduced O2availability in mammals, including angiogenesis, erythropoiesis, and glycolysis. HIF-1 activity is controlled by the O2-regulated expression of the HIF-1α subunit. Under nonhypoxic conditions, HIF-1α protein is subject to ubiquitination and proteasomal degradation. Here we report that missense mutations and/or deletions involving several different regions of HIF-1α result in constitutive expression and transcriptional activity in nonhypoxic cells. We demonstrate that hypoxia results in decreased ubiquitination of HIF-1α and that missense mutations increase HIF-1α expression under nonhypoxic conditions by blocking ubiquitination.