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Inhibition of protein kinase C suppresses megakaryocytic differentiation
and stimulates erythroid differentiation in HEL cells
Y Hong, JF Martin, W Vainchenker and JD Erusalimsky
Department of Medicine, King's College School of Medicine and Dentistry,
London, UK.
The bisindolylmaleimide, GF109203X (2-[1-(3-dimethylaminopropyl)-1H-
indol-3-yl]-3-(1H-indol-3-yl)-maleimide ), a highly selective inhibitor of
protein kinase C (PKC), was used to test the role of this enzyme in phorbol
ester-induced megakaryocytic differentiation of HEL cells. Treatment of
these cells with 10 nmol/L phorbol 12-myristate 13-acetate (PMA) for 3 days
caused a complete inhibition of proliferation and a threefold increase in
the surface expression of glycoprotein (GP) IIIa, a marker of
megakaryocytic differentiation that forms part of the fibrinogen receptor
complex, GPIIb/IIIa. A similar effect was observed with phorbol
12,13-dibutyrate, but not with the biologically inactive derivative
PMA-4-O-methyl ether. The PMA-induced increase in GPIIIa expression was
completely inhibited by GF109203X in a dose-dependent manner (IC50 = 0.5
mumol/L), with a maximal effect at 2.5 to 5.0 mumol/L. GF109203X also
blocked the inhibitory effect of PMA on cell growth and inhibited
PMA-stimulated phosphorylation of the 47-kD PKC substrate, pleckstrin.
Incubation of HEL cells with 25 mumol/L hemin for 3 days caused a fourfold
to fivefold increase in expression of the erythroid differentiation marker,
glycophorin A. In contrast to the inhibitory effect of GF109203X on GPIIIa
expression, hemin induction of glycophorin A was enhanced by this compound.
Furthermore, GF109203X alone caused a dose-dependent increase in
glycophorin A expression, and induced hemoglobinization. Consistent with
these changes, Northern blot analysis revealed that GF109203X treatment
reduced the steady-state level of GPIIb mRNA and increased those for
glycophorin A and gamma- globin. These results suggest that PKC may act as
a developmental switch controlling erythroid/megakaryocytic
differentiation.
Volume 87,
Issue 1,
pp. 123-131,
01/01/1996
Copyright © 1996 by The American Society of Hematology
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