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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-1434

Wanner, R M; Spielmann, P; Stroka, D M; Camenisch, G; Camenisch, I; Scheid, A; Houck, D R; Bauer, C; Gassmann, M; Wenger, R H (2000). Epolones induce erythropoietin expression via hypoxia-inducible factor-1 alpha activation. Blood, 96(4):1558-1565.

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Abstract

Induction of erythropoietin (Epo) expression under hypoxic conditions is mediated by the heterodimeric hypoxia-inducible factor (HIF)-1. Following binding to the 3' hypoxia-response element (HRE) of the Epo gene, HIF-1 markedly enhances Epo transcription. To facilitate the search for HIF-1 (ant)agonists, a hypoxia-reporter cell line (termed HRCHO5) was constructed containing a stably integrated luciferase gene under the control of triplicated heterologous HREs. Among various agents tested, we identified a class of substances called epolones, which induced HRE-dependent reporter gene activity in HRCHO5 cells. Epolones are fungal products known to induce Epo expression in hepatoma cells. We found that epolones (optimal concentration 4-8 micromol/L) potently induce HIF-1 alpha protein accumulation and nuclear translocation as well as HIF-1 DNA binding and reporter gene transactivation. Interestingly, the activity of a compound related to the fungal epolones, ciclopirox olamine (CPX), was blocked after addition of ferrous iron. This suggests that CPX might interfere with the putative heme oxygen sensor, as has been proposed for the iron chelator deferoxamine mesylate (DFX). However, about 10-fold higher concentrations of DFX (50-100 micromol/L) than CPX were required to maximally induce reporter gene activity in HRCHO5 cells. Moreover, structural, functional, and spectrophotometric data imply a chelator:iron stoichiometry of 1:1 for DFX but 3:1 for CPX. Because the iron concentration in the cell culture medium was determined to be 16 micromol/L, DFX but not CPX function can be explained by complete chelation of medium iron. These results suggest that the lipophilic epolones might induce HIF-1 alpha by intracellular iron chelation. (Blood. 2000;96:1558-1565)

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
DDC:570 Life sciences; biology
Language:English
Date:2000
Deposited On:11 Feb 2008 13:23
Last Modified:27 Nov 2013 20:55
Publisher:American Society of Hematology
ISSN:0006-4971
Additional Information:This research was originally published in Blood, 2000; 96(4):1558-65. Copyright by the American Society of Hematology
Related URLs:http://bloodjournal.hematologylibrary.org/cgi/content/abstract/96/4/1558
PubMed ID:10942406
Citations:Web of Science®. Times Cited: 63
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