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Transcriptional and posttranscriptional regulation of the expression of the
erythropoietin receptor gene in human erythropoietin-responsive cell lines
AR Migliaccio, Y Jiang, G Migliaccio, S Nicolis, S Crotta, A Ronchi, S Ottolenghi and JW Adamson
New York Blood Center, NY 10021.
With erythroid differentiation, committed progenitor cells acquire the
ability to respond to erythropoietin (Epo). Epo interacts with target cells
through the Epo receptor (Epo-R), whose expression is tightly regulated in
a lineage-specific fashion. Epo-R expression is presumed to be
progressively activated or repressed as cells progress along the erythroid
or the myeloid pathway, respectively. Little is known of the mechanisms
that underlie the erythroid-specific expression of the Epo-R gene. GATA-1,
the major known transcription factor involved in Epo-R gene regulation, is
not erythroid-specific. We have studied the regulation of the expression of
the Epo-R gene in two related human Epo- responsive cell lines, UT-7 and
UT-7 Epo. These lines express Epo-R at high levels because of amplification
of the endogenous gene, which is apparently not rearranged. Treatment for 6
to 24 hours with the tumor promoter, phorbol myristate acetate (PMA), or 24
hours of growth factor starvation (Epo or granulocyte/macrophage
colony-stimulating factor [GM- CSF]) decreased or increased the levels of
Epo-R mRNA, respectively. In the case of growth factor starvation, the
increase (approximately equal to threefold) in the level of Epo-R mRNA
correlated directly with an increase in the rate of Epo-R gene
transcription as measured by run-off assay. Both increases were observed as
early as 3 hours after the growth factor was withdrawn and were reversible;
levels of mRNA and transcription rates returned to baseline 3 hours after
the cells were reexposed to growth factors. The changes in Epo-R expression
after growth factor starvation were coordinated with changes in the level
of expression of GATA-1 that were detected both at the mRNA and at the gene
transcription level under these conditions (suggesting that GATA-1 was
responsible for this upregulation). During PMA treatment, after a transient
increase in Epo-R mRNA at 1 hour, a progressive decline in the level of
Epo-R mRNA was observed; the level of Epo-R mRNA decreased by 50%, and fell
below the level of detection by 6 and 24 hours, respectively. This
decrement was explained in part by a fourfold reduction in the rate of gene
transcription as well as a reduction (measured as levels of Epo-R mRNA in
the presence of actinomycin D) in mRNA stability. The changes in
transcription rate occurred in the absence of changes in the level of
GATA-1 binding activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 82,
Issue 12,
pp. 3760-3769,
12/15/1993
Copyright © 1993 by The American Society of Hematology
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