Modulation of transduced erythropoietin expression by iron

Future prospects for gene therapy of chronic anemias involve expression of the erythropoietin transgene, which is regulated by oxygen tension. However, other factors such as cytokines or the iron load of erythropoietin-expressing cells can concomitantly modulate transgene expression, as shown for th...

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Bibliographic Details
Published in:Experimental hematology 2000-07, Vol.28 (7), p.760-764
Main Authors: Dalle, Bruno, Payen, Emmanuel, Beuzard, Yves
Format: Article
Language:English
Subjects:
Animals
Cell Line
Erythropoietin
Erythropoietin - biosynthesis
Erythropoietin - genetics
Gene Expression Regulation - drug effects
Gene Transfer Techniques
Genetic Therapy
Hemin - pharmacology
Humans
Hypoxia
Iron
Iron - pharmacology
Iron Chelating Agents - pharmacology
Mice
Mice, Inbred C3H
Oxygen Consumption
Pyridones - pharmacology
Regulation
Transgene
Transgenes
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Summary:Future prospects for gene therapy of chronic anemias involve expression of the erythropoietin transgene, which is regulated by oxygen tension. However, other factors such as cytokines or the iron load of erythropoietin-expressing cells can concomitantly modulate transgene expression, as shown for the expression of the endogenous erythropoietin gene in human cell lines and in animals. We tested the effects of iron overload or depletion on the expression of the mouse erythropoietin transgene (cDNA), driven by the hypoxia-regulated phosphoglycerate kinase 1 promoter. Retrovirally transduced mouse cells (C3H fibroblasts or C2C12 myoblasts) were cultured in normoxia (room air, O 2: 21%) or hypoxia (O 2: 1.5%) in the presence or absence of hemin (an iron donor) or deferiprone (an iron chelator), both of which easily enter the cell. Hemin inhibited the hypoxia-induced expression of the transgene. In contrast, deferiprone enhanced the hypoxia-induced expression of the erythropoietin transgene and induced its expression in normoxia. These results show that, in addition to oxygen partial pressure, the intracellular iron content is critical in the modulation of hypoxia-regulated erythropoietin transgene expression.
ISSN:0301-472X
1873-2399
DOI:10.1016/S0301-472X(00)00174-0