Erythropoietin: A model system for studying oxygen-dependent gene regulation
Bunn, HF; Gu, J; Huang, LE; Park, JW; Zhu, H
HERO ID
1857390
Reference Type
Journal Article
Subtype
Review
Year
1998
Language
English
PMID
| HERO ID | 1857390 |
|---|---|
| Material Type | Review |
| In Press | No |
| Year | 1998 |
| Title | Erythropoietin: A model system for studying oxygen-dependent gene regulation |
| Authors | Bunn, HF; Gu, J; Huang, LE; Park, JW; Zhu, H |
| Journal | Journal of Experimental Biology |
| Volume | 201 |
| Issue | 8 |
| Page Numbers | 1197-1201 |
| Abstract | The physiological regulation of the red cell mass depends upon enhanced transcription of the erythropoietin (Epo) gene in response to hypoxia. Studies of Epo gene expression have been useful in investigating the mechanism by which cells and tissues sense hypoxia and respond with biologically appropriate alterations in gene expression. It is likely that oxygen sensing involves a heme protein in which cobalt and nickel can substitute for iron in the porphyrin ring. Indirect evidence suggests that the sensor is present in all cells and is a multi-subunit assembly containing an NAD(P)H oxidase capable of generating peroxide and reactive oxygen intermediates, which serve as signaling molecules. The up-regulation of Epo gene transcription by hypoxia is mediated by at least two known DNA-binding transcription factors, hypoxia-inducible factor 1 (HIF-1) and hepatic nuclear factor 4 (HNF-4), which bind to cognate response elements in a critical 3' enhancer approximately 50 bp in length. HIF-1 binding is induced by hypoxia as well as by cobalt. The activation of HIF-1 by hypoxia depends upon the selective protection of its alpha subunit from ubiquitin-dependent proteolysis by means of a mechanism that involves redox chemistry and perhaps phosphorylation. HNF-4 is an orphan nuclear receptor that is constitutively expressed in kidney and liver and which cooperates with HIF-1 to give maximal hypoxic induction. In hypoxic cells, p300 or a related family member forms a macromolecular assembly with HIF-1 and HNF-4, enabling transduction from the Epo 3' enhancer to the apparatus on the promoter responsible for the initiation of transcription. |
| Doi | 10.1242/jeb.201.8.1197 |
| Pmid | 9510530 |
| Wosid | WOS:000073772900013 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | erythropoietin; hypoxia; gene regulation; oxygen sensing; HIF-1; HNF-4; p300 |