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Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1

Cited 56 time in Web of Science Cited 61 time in Scopus
Authors
Yeo, Eun-Jin; Ryu, Ji-Hye; Cho, Young-Suk; Chun, Yang-Sook; Huang, L. Eric; Kim, Myung-Suk; Park, Jong-Wan
Issue Date
2005-09-29
Publisher
American Society of Hematology
Citation
Blood. 2006 Feb 1;107(3):916-23. Epub 2005 Sep 27.
Keywords
Amphotericin B/*administration & dosage/adverse effectsAnemia/chemically induced/metabolismAnimalsAnoxia/*metabolismAntifungal Agents/*administration & dosage/adverse effectsCell LineDown-Regulation/drug effectsE1A-Associated p300 Protein/metabolismErythropoietin/*biosynthesisHumansHypoxia-Inducible Factor 1, alpha Subunit/*metabolismKidney/metabolismMaleMycoses/complications/drug therapy/metabolismProtein Structure, TertiaryRatsRats, Sprague-DawleyRepressor Proteins/*antagonists & inhibitors/metabolismTranscription, Genetic/drug effects
Abstract
Amphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1alpha, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1alpha, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.
ISSN
0006-4971 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16189267

http://hdl.handle.net/10371/29630
DOI
https://doi.org/10.1182/blood-2005-06-2564
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Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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