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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1374-1381
HEMATOPOIESIS
Growth factor withdrawal from primary human erythroid progenitors
induces apoptosis through a pathway involving glycogen synthase
kinase-3 and Bax
Tim C. P. Somervaille,
David C. Linch, and
Asim Khwaja
From the Department of Hematology, Royal Free and
University College Medical School, London, United Kingdom.
The prevention of apoptosis is a key function of growth
factors in the regulation of erythropoiesis. This study examined the role of the constitutively active serine/threonine kinase glycogen synthase kinase-3 (GSK3), a target of the phosphoinositide-3-kinase (PI3K)/Akt pathway, in the regulation of apoptosis in primary human
erythroid progenitors. GSK3 phosphorylation at its key regulatory residues S21 ( isoform) and S9 ( isoform) was high in
steady-state culture, disappeared on growth factor withdrawal, and
returned in response to treatment of cells with either erythropoietin
or stem cell factor. Phosphorylation correlated with a PI3K-dependent reduction of 25% to 30% in measured GSK3 activity. LY294002, a specific inhibitor of PI3K, induced apoptosis in growth
factor-replete erythroid cells to a degree similar to growth
factor deprivation, whereas the Mek1 inhibitor U0126 had no effect,
implicating PI3K and not mitogen-activated protein kinase in survival
signaling. Growth factor-deprived erythroblasts, which undergo
apoptosis rapidly, were protected from apoptosis by both lithium
chloride, a GSK3 selective inhibitor, and inhibition of caspase
activity. However, the clonogenic potential of single cells, which more accurately reflects cell survival, was maintained by lithium chloride, but not by caspase inhibition. Furthermore, lithium chloride, but not
caspase inhibition, prevented the appearance of the conformational form
of Bax associated with apoptosis induction. In summary, GSK3 activity
is suppressed by erythropoietin and stem cell factor in human erythroid
progenitor cells, and increased GSK3 activity, brought about by growth
factor withdrawal, may regulate commitment to cell death through a
caspase-independent pathway that results in a conformational change
in Bax.
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