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

作者：Thomas R. Sutter, Erik Laughner, Gregg L. Semenza · 发表于：Proceedings of the National Academy of Sciences · 年份：2000 · DOI：10.1073/pnas.080072497 · 被引用次数：298 · 研究领域：Cancer, Hypoxia, and Metabolism、High Altitude and Hypoxia、Adipose Tissue and Metabolism

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.