Serum response factor cleavage by caspases 3 and 7 linked to apoptosis in human BJAB cells

Apoptosis involves the cessation of cellular processes, the breakdown of in tracellular organelles, and, finally, the nonphlogistic clearance of apopto tic cells from the body. Important for these events is a family of protease s, caspases, which are activated by a proteolytic cleavage cascade and driv e apoptosis by targeting key proteins within the cell. Here, we demonstrate that serum response factor (SRF), a transcription factor essential for pro liferative gene expression, is cleaved by caspases and that this cleavage o ccurs in proliferating murine fibroblasts and can be induced in the human B -cell line BJAB. We identify the two major sites at which SRF cleavage occu rs as Asp(245) and Asp(254), the caspases responsible for the cleavage and generate a mutant of SRF resistant to cleavage in BJAB cells. Investigation of the physiological and functional significance of SRF cleavage reveals t hat it correlates with the loss of e-fos expression, whereby neither SRF cl eavage fragment retains transcriptional activity. Moreover, the expression of a noncleavable SRF in BJAB cells suppresses apoptosis induced by Fas cro ss-linking. These results suggest that for apoptosis to proceed, the transc riptional events promoting cell survival and proliferation, in which SRF is involved, must first be inactivated.