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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1768-1775
Phosphorylation of BCL-2 After Exposure of Human Leukemic Cells
to Retinoic Acid
Z.-B. Hu,
M.D. Minden, and
E.A. McCulloch
From The Ontario Cancer Institute and Princess Margaret Hospital,
Toronto, Canada.
Serine phosphorylation of bcl-2 has been reported after treatment of
cells with protein kinase C, okadaic acid, taxol, and other
chemotherapeutic agents that attack microtubules. We report here that
bcl-2 is phosphorylated on serine in acute myeloblastic leukemia (AML)
blasts exposed to all trans retinoic acid (ATRA). Two-dimension gels
(isoelectric focusing followed by sodium dodecyl sulfate-polyacrylamide
gel electrophoresis [SDS-PAGE]) disclosed a novel acidic isoform of
bcl-2 in ATRA-treated blast cells from a continuous line and from two
AML patients; when the cell lysates were digested with  -phosphatase,
bcl-2 reverted to the control position, indicating that it was
phosphorylated. Metabolic labeling experiments using
32Pi showed that, while control bcl-2 was
labeled, incorporation was greatly increased when cells were treated
with ATRA. A comparison of bcl-2 from blasts treated with ATRA or taxol
showed that bcl-2 was phosphorylated on serine in cells treated with
either agent; however, both qualitative and quantitative differences
were seen. Qualitatively, the phosphorylated isoform from taxol-treated
cells was slightly larger than the native isoform and could be
distinguished on 10% to 20% SDS-polyacrylamide gradient gels, while
the phosphorylated bcl-2 after ATRA ran as a single band on gradient
gels at the same position as control bcl-2. Quantitatively, all bcl-2
from ATRA-treated cells was in the phosphorylated isoform, while after taxol, both phosphorylated and native bcl-2 was present; incorporation of 32Pi into bcl-2 was stimulated to greater
extent in ATRA-treated compared with taxol-treated cells. We used
immunoprecipitation experiments to ask if bcl-2 phosphorylated after
ATRA or taxol had altered capacity to dimerize with bax. No change in
dimerization was demonstrated. We conclude that: bcl-2 is
phosphorylated on serine after treatment of AML blasts with ATRA; bcl-2
phosphorylation after ATRA is different from that seen after taxol;
bcl-2 phosphorylated after either agent retains capacity to dimerize
with bax. The ATRA or taxol-induced phosphorylation of bcl-2 can also
be seen in blast cells obtained from AML patients.
© 1998 by The American Society of Hematology.
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