Hypoxia-inducible factor 1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations

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.