期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：14
页码：7987-7992
DOI：10.1073/pnas.95.14.7987
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Hypoxia induces a group of physiologically important genes such as erythropoietin and vascular endothelial growth factor. These genes are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1), a global regulator that belongs to the basic helix-loop-helix PAS family. Although HIF-1 is a heterodimer composed of and {beta} subunits, its activity is primarily determined by hypoxia-induced stabilization of HIF-1, which is otherwise rapidly degraded in oxygenated cells. We report the identification of an oxygen-dependent degradation (ODD) domain within HIF-1 that controls its degradation by the ubiquitin-proteasome pathway. The ODD domain consists of {approx}200 amino acid residues, located in the central region of HIF-1. Because portions of the domain independently confer degradation of HIF-1, deletion of this entire region is required to give rise to a stable HIF-1, capable of heterodimerization, DNA-binding, and transactivation in the absence of hypoxic signaling. Conversely, the ODD domain alone confers oxygen-dependent instability when fused to a stable protein, Gal4. Hence, the ODD domain plays a pivotal role for regulating HIF-1 activity and thereby may provide a means of controlling gene expression by changes in oxygen tension.
