DOI: 10.1182/blood-2005-06-2564. Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1

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

10.1182/blood-2005-06-2564

Crossref journal-article

American Society of Hematology

Blood (234)

Abstract

AbstractAmphotericin 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-1α, 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-1α, 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.

Bibliography

Yeo, E.-J., Ryu, J.-H., Cho, Y.-S., Chun, Y.-S., Huang, L. E., Kim, M.-S., & Park, J.-W. (2006). Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1. Blood, 107(3), 916â923.

Authors 7

Eun-Jin Yeo (first)
Ji-Hye Ryu (additional)
Young-Suk Cho (additional)
Yang-Sook Chun (additional)
L. Eric Huang (additional)
Myung-Suk Kim (additional)
Jong-Wan Park (additional)

References 40 Referenced 74

Dates

Type	When
Created	19 years, 11 months ago (Sept. 27, 2005, 11:33 p.m.)
Deposited	5 years, 4 months ago (April 9, 2020, 7:27 p.m.)
Indexed	2 months ago (June 28, 2025, 5:03 a.m.)
Issued	19 years, 7 months ago (Feb. 1, 2006)
Published	19 years, 7 months ago (Feb. 1, 2006)
Published Print	19 years, 7 months ago (Feb. 1, 2006)

Funders 0

None

BibTeX

@article{Yeo_2006, title={Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1}, volume={107}, ISSN={1528-0020}, url={http://dx.doi.org/10.1182/blood-2005-06-2564}, DOI={10.1182/blood-2005-06-2564}, number={3}, journal={Blood}, publisher={American Society of Hematology}, author={Yeo, Eun-Jin and Ryu, Ji-Hye and Cho, Young-Suk and Chun, Yang-Sook and Huang, L. Eric and Kim, Myung-Suk and Park, Jong-Wan}, year={2006}, month=feb, pages={916–923} }

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  "abstract": "<jats:title>Abstract</jats:title><jats:p>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-1\u03b1, 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-1\u03b1, 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.</jats:p>",
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