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Blood, 15 July 2002, Vol. 100, No. 2, pp. 467-473
HEMATOPOIESIS
Prostaglandin-E2 enhances EPO-mediated STAT5
transcriptional activity by serine phosphorylation of CREB
Arjen-Kars Boer,
A. Lyndsay Drayer,
Hallgeir Rui, and
Edo Vellenga
From the Division of Hematology, Department of
Medicine, University Hospital Groningen, Groningen, The Netherlands;
Bloodbank Noord Nederland, Groningen, The Netherlands; and Department
of Pathology, Uniformed Services University of the Health Sciences,
Bethesda, MD.
Erythroid colony formation in response to erythropoietin (EPO)
stimulation is enhanced by costimulating the cells with
prostaglandin-E2 (PGE2). The present study
further analyzed the underlying mechanisms and demonstrated that
EPO-mediated STAT5 transactivation in the erythroid AS-E2 cell line was
enhanced 6-fold by PGE2 (10 µM), without affecting the
STAT5 tyrosine phosphorylation or STAT5-DNA binding. Moreover, the
PGE2-enhancing effect was independent of STAT5 serine
phosphorylation. In AS-E2 cells STAT5 is constitutively phosphorylated
on Ser780 (STAT5A) and EPO-dependently phosphorylated on Ser726/731
(STAT5A/STAT5B), but overexpression of STAT5 serine mutants did not
affect STAT5 transactivation. In addition, PGE2 did not
affect STAT5 serine phosphorylation. Instead, the stimulatory effect of
PGE2 on STAT5 signaling could be mimicked by
dibutyryl-cyclic adenosine monophosphate (cAMP) and the
phosphodiesterase inhibitor IBMX, suggesting that the effect was
mediated by cAMP. Activation of the cAMP pathway
resulted in cAMP-response element binding protein (CREB)
phosphorylation, which was sustained in the presence of EPO plus
PGE2 and transient on EPO stimulation alone. The
costimulatory effect of PGE2 on EPO-mediated STAT5
transactivation was inhibited by overexpression of serine-dead CREB or
protein kinase A (PKA) inhibitor (PKI), in contrast to EPO-mediated
transactivation, which was PKA independent. Furthermore,
CREB-binding protein (CBP)/p300 was shown to be involved in
EPO-mediated STAT5 transactivation, and a CBP mutant with increased
affinity for CREB resulted in an additional enhancement of the
PGE2 effect. Finally, we demonstrated that the
STAT5 target genes Bcl-X, SOCS2, and
SOCS3 were up-regulated by costimulation with
PGE2. In summary, these studies demonstrate that
PGE2 enhancement of EPO-induced STAT5 transactivation is mediated by the cAMP/PKA/CREB pathway.
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