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Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted
C H Sutter1, E Laughner, G L Semenza
1Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-3914, USA.
Abstract:
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-1alpha subunit. Under nonhypoxic conditions, HIF-1alpha protein is subject to ubiquitination and proteasomal degradation. Here we report that missense mutations and/or deletions involving several different regions of HIF-1alpha result in constitutive expression and transcriptional activity in nonhypoxic cells. We demonstrate that hypoxia results in decreased ubiquitination of HIF-1alpha and that missense mutations increase HIF-1alpha expression under nonhypoxic conditions by blocking ubiquitination.