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The Induction of Megakaryocyte Differentiation Is Accompanied by
Selective Ser133 Phosphorylation of the Transcription
Factor CREB in Both HEL Cell Line and Primary CD34+
Cells
Giorgio Zauli,
Davide Gibellini,
Marco Vitale,
Paola Secchiero,
Claudio Celeghini,
Alessandra Bassini,
Sabina Pierpaoli,
Marco Marchisio,
Lia Guidotti, and
Silvano Capitani
From the Institute of Human Anatomy, University of Ferrara, Ferrara,
Italy; the Institute of Microbiology and the Institute of Histology and
General Embriology, University of Bologna, Bologna, Italy; and the
Department of Biomedical Sciences and Biotechnology, Human Anatomy
Section, University of Brescia, Brescia, Italy.
The addition of thrombopoietin (TPO) to HEL cells, cultured in a
chemically defined serum-free medium, induced a rapid and dose-dependent phosphorylation of the transcription factor CREB on
serine133 (PSer133), as detected by Western
blot analysis. TPO also significantly increased the transactivation of
CRE-dependent promoter, as determined in transient transfection
experiments. On the other hand, neither erythropoietin (Epo; 1 to 10 U)
nor hemin (10 7 mol/L) were able to significantly
stimulate CREB-PSer133 or to activate CRE-promoter in HEL
cells. Although pharmacological inhibitors of protein kinase C
(chelerytrine and BIM) and protein kinase A (H-89) failed to block the
TPO-mediated CREB phosphorylation, a specific inhibitor of the
mitogen-activated protein kinases (PD98059) completely blocked the
ability of TPO to stimulate CREB-PSer133. Moreover, PD98059
significantly decreased the ability of TPO to upregulate the surface
expression of the  IIb 3 megakaryocytic marker in HEL
cells. In parallel, primary CD34+ hematopoietic cells
were seeded in liquid cultures supplemented with 100 ng/mL of TPO and
examined by immunofluorescence for the coexpression of
IIb3 and CREB-PSer133 at various time
points. High levels of nuclear CREB-PSer133 were
unequivocally demonstrated in IIb3+
cells, including morphologically recognizable megakaryocytes. Taken
together, these data suggest that CREB plays a role in modulating the
expression of genes critical for megakaryocyte differentiation and that
the TPO-mediated CREB phosphorylation seems to be regulated via
mitogen-activated protein kinases.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 472-480
© 1998 by the American Society of Hematology.
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