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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kim, William Y. Flippin, Lee Günzler, Volkmar Depinho, Ronald A. Safran, Michal O'connell, Fionnuala Horner, James W. Kaelin, William G. |
| Description | Author Affiliation: Safran M ( Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.); |
| Abstract | Many human diseases are characterized by the development of tissue hypoxia. Inadequate oxygenation can cause cellular dysfunction and death. Tissues use many strategies, including induction of angiogenesis and alterations in metabolism, to survive under hypoxic conditions. The heterodimeric transcription factor hypoxia-inducible factor (HIF) is a master regulator of genes that promote adaptation to hypoxia. HIF activity is linked to oxygen availability because members of the EGLN family hydroxylate HIFalpha subunits on specific prolyl residues when oxygen is present, which marks them for ubiquitination and proteasomal degradation. We created a mouse that ubiquitously expresses a bioluminescent reporter consisting of firefly luciferase fused to a region of HIF that is sufficient for oxygen-dependent degradation. Our validation studies suggest that this mouse will be useful for monitoring hypoxic tissues and evaluating therapeutic agents that stabilize HIF. One such agent, the HIF prolyl hydroxylase inhibitor FG-4383, was active in the liver and kidney after systemic administration as determined by bioluminescence imaging, transcription profiling, and production of erythropoietin, indicating that the HIF transcriptional program can be manipulated in vivo with orally active organic small molecules. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 1 |
| Volume Number | 103 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2006-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Dioxygenases Antagonists & Inhibitors Metabolism Enzyme Inhibitors Erythropoietin Biosynthesis Hypoxia-Inducible Factor 1 Models, Animal Animals Cell Hypoxia Physiology Cells, Cultured DNA Primers DNA, Complementary Genetics Enzyme-Linked Immunosorbent Assay Hypoxia-Inducible Factor-Proline Dioxygenases Luciferases Mice Molecular Probe Techniques Plasmids Proteins RNA, Untranslated Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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