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(Received for publication, March 10, 1997)
From the Sealy Center for Oncology and Hematology and Department of
Internal Medicine, University of Texas Medical Branch, Galveston, Texas
77555-1048
The protooncogene Bcl-2 functions as a suppressor
of apoptosis in growth factor-dependent cells, but a
post-receptor signaling mechanism is not known. We recently reported
that interleukin 3 (IL-3) and erythropoietin, or the protein kinase C
activator bryostatin-1 (Bryo), not only suppresses apoptosis but also
stimulates the phosphorylation of Bcl-2 (May, W. S., Tyler, P. G., Ito,
T., Armstrong, D. K., Qatsha, K. A., and Davidson, N. E. (1994)
J. Biol. Chem. 269, 26865-26870). To test whether
phosphorylation is required for Bcl-2 function, conservative serine
Volume 272, Number 18,
Issue of May 2, 1997
pp. 11671-11673
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
alanine mutations were produced at the seven putative protein kinase C phosphorylation sites in Bcl-2. Results indicate that the S70A Bcl-2
mutant fails to be phosphorylated after IL-3 or Bryo stimulation and is
unable to support prolonged cell survival either upon IL-3 deprivation
or etoposide treatment when compared with wild-type Bcl-2. In contrast,
a Ser Glu mutant, S70E, which may mimic a potential phosphate
charge, more potently suppressed the etoposide-induced apoptosis than
wild type in the absence of IL-3. Since the loss of function S70A
mutant can heterodimerize with its partner protein and death effector
Bax, these findings demonstrate that Bcl-2:Bax heterodimerization is
not sufficient and Bcl-2 phosphorylation is required for full Bcl-2
death suppressor signaling activity.
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