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J Biol Chem, Vol. 273, Issue 28, 17926-17932, July 10, 1998
From the The BCL-2 proto-oncogene contains
unusually long untranslated 5' and 3' sequences. Deletion of the
sequences flanking the BCL-2 open reading frame dramatically increases
the level of protein expression. Transient high level BCL-2 protein
expression mediated by plasmid transfection or by infection with
recombinant adenovirus results in potent apoptosis of several cell
lines. Detailed mutational (deletion and add-back) analysis reveals
that both 5'- and 3'-flanking sequences contribute to the negative
modulation of protein expression from the BCL-2 open reading frame. It
appears that these sequences exert the negative regulatory effect in an
orientation-dependent manner. Analysis of BCL-2
RNA levels indicate that elevated levels of mRNA may be the primary
cause of elevated levels of protein expression. Apoptosis induced by
adenovirus vectors expressing elevated levels of BCL-2 can be readily
inhibited by the caspase inhibitor z-VAD-fmk, suggesting that high
levels of BCL-2 expression induce apoptosis via the caspase cascade.
Mutational analysis of BCL-2 indicates that its pro-apoptotic activity
is separable from its anti-apoptosis activity. Our results raise the
possibility that oncogenic conversion of BCL-2 may require somatic
mutations in the pro-apoptotic activity, in addition to other
activating mutations that result in enhanced expression. Consistent
with this hypothesis, a somatic mutation of BCL-2 observed
in multiple human tumors results in reduced apoptosis activity.
A Potent Cell Death Activity Associated with Transient High Level
Expression of BCL-2
,,
Institute for Molecular Virology, Saint
Louis University Health Sciences Center, St. Louis, Missouri 63110 and ¶ Apoptosis Technology, Inc.,
Cambridge, Massachusetts 02139
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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