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Blood, 1 May 2001, Vol. 97, No. 9, pp. 2863-2871
RED CELLS
Repression of ferritin expression increases the labile iron pool,
oxidative stress, and short-term growth of human
erythroleukemia cells
Or Kakhlon,
Yosef Gruenbaum, and
Zvi Ioav Cabantchik
From the Departments of Biological Chemistry and of
Genetics, Institute of Life Sciences, Hebrew University, Jerusalem,
Israel.
The role of ferritin expression on the labile iron pool of cells
and its implications for the control of cell proliferation were
assessed. Antisense oligodeoxynucleotides were used as tools for
modulating the expression of heavy and light ferritin subunits of K562
cells. mRNA and protein levels of each subunit were markedly reduced by
2-day treatment with antisense probes against the respective subunit.
Although the combined action of antisense probes against both subunits
reduced their protein expression, antisense repression of one subunit
led to an increased protein expression of the other. Antisense
treatment led to a rise in the steady-state labile iron pool, a rise in
the production of reactive oxygen species after pro-oxidative
challenges and in protein oxidation, and the down-regulation of
transferrin receptors. When compared to the repression of individual subunits, co-repression of each subunit evoked a more than additive increase in the labile iron pool and the extent of protein oxidation. These treatments had no detectable effects on the long-term growth of
cells. However, repression of ferritin synthesis facilitated the
renewal of growth and the proliferation of cells pre-arrested at the
G1/S phase. Renewed cell growth was significantly less dependent on external iron supply when ferritin synthesis was repressed
and its degradation inhibited by lysosomal antiproteases. This study
provides experimental evidence that links the effect of ferritin
repression on growth stimulation to the expansion of the labile iron pool.

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