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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Huang, L. Eric To, Kenneth K. W. |
| Description | Author Affiliation: To KK ( Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, MD 20892, USA.) |
| Abstract | The cellular response to hypoxia is, at least in part, mediated by the transcriptional regulation of hypoxia-responsive genes involved in balancing the intracellular ATP production and consumption. Recent evidence suggests that the transcription factor, HIF-1alpha, functions as a master regulator of oxygen homeostasis by controlling a broad range of cellular events in hypoxia. In normoxia, HIF-1alpha is targeted for destruction via prolyl hydroxylation, an oxygen-dependent modification that signals for recognition by the ubiquitin ligase complex containing the von Hippel-Lindau tumor suppressor. Three HIF prolyl hydroxylases (EGLN1, EGLN2, and EGLN3) have been identified in mammals, among which EGLN1 and EGLN3 are hypoxia-inducible at their mRNA levels in an HIF-1alpha-dependent manner. In this study, we demonstrated that apart from promoting HIF-1alpha proteolysis in normoxia, EGLN1 specifically represses HIF-1alpha transcriptional activity in hypoxia. Ectopic expression of EGLN1 inhibited HIF-1alpha transcriptional activity without altering its protein levels in a von Hippel-Lindau-deficient cell line, indicating a discrete activity of EGLN1 in transcriptional repression. Conversely, silencing of EGLN1 expression augmented HIF-1alpha transcriptional activity and its target gene expression in hypoxia. Thus, we proposed that the accumulated EGLN1 in hypoxia acts as a negative-feedback mechanism to modulate HIF-1alpha target gene expression. Our finding also provided new insight into the pharmacological manipulation of the HIF prolyl hydroxylase for ischemic diseases. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 45 |
| Volume Number | 280 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2005-11-11 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Gene Silencing Hypoxia-Inducible Factor 1, Alpha Subunit Antagonists & Inhibitors Metabolism Immediate-Early Proteins Procollagen-Proline Dioxygenase Transcription, Genetic Animals Cell Line Genes, Reporter Genetics Hypoxia-Inducible Factor-Proline Dioxygenases Oxygen Pharmacology Protein Binding Drug Effects Research Support, N.I.H., Intramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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