Failure of gelsolin overexpression to regulate lymphocyte apoptosis

The actin regulatory protein gelsoiin cleaves actin filaments in a calcium- and polyphosphoinositide-dependent manner. Gelsolin has recently been desc ribed as a novel substrate of the cysteinyl protease caspase-3, an effector protease activated during apoptosis. Cleavage by caspase-3 generates an am ino-terminal fragment of gelsolin that can sever actin filaments independen tly of calcium regulation. The disruption of the actin cytoskeleton by clea ved gelsolin is hypothesized to mediate many of the downstream morphologica l changes associated with apoptosis. In contrast, overexpression of full-le ngth gelsolin has also been re-ported to inhibit apoptotic cell death upstr eam of the activation of caspase-3, suggesting that gelsolin may also act p rior to commitment to cell death. The authors previously observed that acti n stabilization by the cell permeant agent jasplakinolide enhanced cell dea th upon interleukin (IL)-2 or IL-3 withdrawal from growth-factor-dependent lymphocyte cell lines, and hypothesized that actin polymerization could alt er the activity of gelsolin, thus enhancing apoptosis. Here the authors sho w that constitutive overexpression of gelsolin did not, however, inhibit or dramatically enhance apoptotic cell death upon growth-factor withdrawal, n or did it modify sensitivity to jasplakinolide, in contrast to previous rep orts, overexpression of gelsolin in Jurkat T cells did not prevent or delay apoptosis induced by Fas ligation or ceramide treatment. Overexpressed gel solin 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. (Blood. 2000;95:3483-3488) (C) 2000 by The American Society of Hematology.