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Protection From Apoptosis by Steel Factor But Not
Interleukin-3 Is Reversed Through Blockade of Calcium Influx
Jennifer L. Gommerman and
Stuart A. Berger
From the Wellesley Hospital Research Institute and Department of
Immunology, University of Toronto, Toronto, Ontario, Canada.
Steel factor (SLF), the ligand for the c-Kit receptor,
protects hemopoietic progenitors and mast cells from apoptosis. We show
here that protection of 32D-Kit cells or mast cells from apoptosis by
SLF is abrogated through concurrent inhibition of Ca2+
influx. In contrast, cell survival promoted by interleukin-3 is not
affected by Ca2+ influx blockers. In the presence of
blockers, increasing stimulation by SLF leads to greater levels of cell
death in the population, indicating that it is the combination of
activation by SLF with concurrent blockade of Ca2+ influx
that results in apoptosis. The p815 mastocytoma, which expresses a
mutated, constitutively active c-kit receptor, dies apoptotically in
the presence of Ca2+ influx blockers alone. Ionomycin
protects cells from SLF plus blocker-induced apoptosis, confirming
specificity for Ca2+ ion blockade in cell death
induction. Overexpression of bcl-2, which protects 32D-Kit cells from
factor withdrawal, does not protect cells from apoptosis by SLF plus
blocker. In contrast, caspase inhibitors YVAD-CHO, DEVD-FMK, and
Boc-Asp-FMK protect cells from SLF plus blocker-induced death. These
observations highlight the importance of SLF-stimulated
Ca2+ influx in the protection of cells from apoptosis and
demonstrate a new mechanism for inducing bcl-2 insensitive,
caspase-dependent apoptosis through the combination of SLF stimulation
with Ca2+ influx blockade.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1891-1900
© 1998 by The American Society of Hematology.
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