S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Physiology (생리학교실) Journal Papers (저널논문_생리학교실)
Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1
- Yeo, Eun-Jin; Ryu, Ji-Hye; Cho, Young-Suk; Chun, Yang-Sook; Huang, L. Eric; Kim, Myung-Suk; Park, Jong-Wan
- Issue Date
- American Society of Hematology
- Blood. 2006 Feb 1;107(3):916-23. Epub 2005 Sep 27.
- Amphotericin B/*administration & dosage/adverse effects; Anemia/chemically induced/metabolism; Animals; Anoxia/*metabolism; Antifungal Agents/*administration & dosage/adverse effects; Cell Line; Down-Regulation/drug effects; E1A-Associated p300 Protein/metabolism; Erythropoietin/*biosynthesis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism; Kidney/metabolism; Male; Mycoses/complications/drug therapy/metabolism; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley; Repressor Proteins/*antagonists & inhibitors/metabolism; Transcription, Genetic/drug effects
- 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.
- 0006-4971 (Print)
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