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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3593-3603
H-Ferritin Subunit Overexpression in Erythroid Cells Reduces the
Oxidative Stress Response and Induces Multidrug Resistance Properties
Silvina Epsztejn,
Hava Glickstein,
Virginie Picard,
Itzchak N. Slotki,
William Breuer,
Carole Beaumont, and
Z. Ioav Cabantchik
From the Department of Biological Chemistry, Institute of Life
Sciences, Hebrew University of Jerusalem, Jerusalem, Isreal; Nephrology
Unit, Shaare Zedek Medical Center, Jerusalem, Israel;
Génétique et Pathologie Moleculaire de
l'Hématopoiese, Faculté Xavier Bichat, Paris, France.
The labile iron pool (LIP) of animal cells has been implicated in
cell iron regulation and as a key component of the oxidative-stress response. A major mechanism commonly implied in the downregulation of
LIP has been the induced expression of ferritin (FT), particularly the
heavy subunits (H-FT) that display ferroxidase activity. The effects of
H-FT on LIP and other physiological parameters were studied in murine
erythroleukemia (MEL) cells stably transfected with H-FT subunits.
Clones expressing different levels of H-FT displayed similar
concentrations of total cell iron (0.3 ± 0.1 mmol/L) and of
reduced/total glutathione. However, with increasing H-FT levels the
cells expressed lower levels of LIP and reactive oxygen species (ROS)
and ensuing cell death after iron loads and oxidative challenges. These
results provide direct experimental support for the alleged roles of
H-FT as a regulator of labile cell iron and as a possible attenuator of
the oxidative cell response. H-FT overexpression was of no apparent
consequence to the cellular proliferative capacity. However,
concomitant with the acquisition of iron and redox regulatory
capacities, the H-FT-transfectant cells commensurately acquired
multidrug resistance (MDR) properties. These properties were identified
as increased expression of MDR1 mRNA (by reverse transcription
polymerase chain reaction [RT-PCR]), P-glycoprotein (Western
immunoblotting), drug transport activity (verapamil-sensitive drug
efflux), and drug cytotoxicity associated with increased MDR1 or PgP.
Although enhanced MDR expression per se evoked no significant changes
in either LIP levels or ROS production, it might be essential for the
survival of H-FT transfectants, possibly by expediting the export of
cell-generated metabolites.
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