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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2084-2092
HEMATOPOIESIS
Phosphatase inhibition promotes antiapoptotic but not
proliferative signaling pathways in erythropoietin-dependent
HCD57 cells
Amy E. Lawson,
Haifeng Bao,
Amittha Wickrema,
Sarah M. Jacobs-Helber, and
Stephen T. Sawyer
From the Department of Pharmacology and Toxicology,
Medical College of Virginia Campus of Virginia Commonwealth University,
Richmond, VA, and Section of Hematology-Oncology, University of
Illinois at Chicago, Chicago, IL.
Erythropoietin (EPO) allows erythroid precursors to proliferate
while protecting them from apoptosis. Treatment of the EPO-dependent HCD57 murine cell line with 70 µmol/L orthovanadate, a tyrosine phosphatase inhibitor, resulted in both increased tyrosine protein phosphorylation and prevention of apoptosis in the absence of EPO
without promoting proliferation. Orthovanadate also delayed apoptosis
in primary human erythroid progenitors. Thus, we investigated what
survival signals were activated by orthovanadate treatment. Expression
of Bcl-XL and BAD phosphorylation are critical for the
survival of erythroid cells, and orthovanadate in the absence of EPO
both maintained expression levels of antiapoptotic Bcl-XL and induced BAD phosphorylation at serine 112. Orthovanadate activated JAK2, STAT1, STAT5, the phosphatidylinositol-3 kinase (PI-3 kinase) pathway, and other signals such as JNK and p38 without activating the
EPO receptor, JAK1, Tyk2, Vav, STAT3, and SHC. Neither JNK nor p38
appeared to have a central role in either apoptosis or survival induced
by orthovanadate. Treatment with cells with LY294002, an inhibitor of
PI-3 kinase activity, triggered apoptosis in orthovanadate-treated cells, suggesting a critical role of PI-3 kinase in
orthovanadate-stimulated survival. Mitogen-activated protein kinase
(MAPK) was poorly activated by orthovanadate, and inhibition of MAPK
with PD98059 blocked proliferation without inducing apoptosis. Thus,
orthovanadate likely acts to greatly increase JAK/STAT and PI-3 kinase
basal activity in untreated cells by blocking tyrosine protein
phosphatase activity. Activated JAK2/STAT5 then likely acts upstream of
Bcl-XL expression and PI-3 kinase likely promotes BAD
phosphorylation to protect from apoptosis. In contrast, MAPK/ERK
activity correlates with only EPO-dependent proliferation but is not
required for survival of HCD57 cells.
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