Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3483-3488
Failure of gelsolin overexpression to regulate lymphocyte
apoptosis
S. Celeste Posey,
Maria Paola Martelli,
Toshifumi Azuma,
David J. Kwiatkowski, and
Barbara E. Bierer
National Heart, Lung, and Blood Institute, National Institutes of
Health, Bethesda, MD; Committee on Immunology, Division of Medical
Sciences, and the Departments of Medicine and Pediatrics, Harvard
Medical School, Boston, MA, Dana-Farber Cancer Institute, Boston, MA;
Genetics Laboratory, Hematology Division, Brigham and Women's
Hospital, Boston, MA.
The actin regulatory protein gelsolin cleaves actin filaments in a
calcium- and polyphosphoinositide-dependent manner. Gelsolin has
recently been described as a novel substrate of the cysteinyl protease
caspase-3, an effector protease activated during apoptosis. Cleavage by
caspase-3 generates an amino-terminal fragment of gelsolin that can
sever actin filaments independently of calcium regulation. The
disruption of the actin cytoskeleton by cleaved gelsolin is
hypothesized to mediate many of the downstream morphological changes
associated with apoptosis. In contrast, overexpression of full-length
gelsolin has also been reported to inhibit apoptotic cell death
upstream of the activation of caspase-3, suggesting that gelsolin may
also act prior to commitment to cell death. The authors previously
observed that actin stabilization by the cell permeant agent
jasplakinolide enhanced cell death upon interleukin (IL)-2 or IL-3
withdrawal from growth-factor-dependent lymphocyte cell lines, and
hypothesized that actin polymerization could alter the activity of
gelsolin, thus enhancing apoptosis. Here the authors show that
constitutive overexpression of gelsolin did not, however, inhibit or
dramatically enhance apoptotic cell death upon growth-factor withdrawal, nor did it modify sensitivity to jasplakinolide. In contrast to previous reports, overexpression of gelsolin in Jurkat T
cells did not prevent or delay apoptosis induced by Fas ligation or
ceramide treatment. Overexpressed gelsolin protein was cleaved during
apoptosis, as seen previously in this and other cell types. In these
model systems, therefore, the level of gelsolin expression was not a
rate-limiting determinant in commitment to or time to the morphological
changes of apoptosis.
