title: Serum response factor cleavage by caspases 3 and 7 linked to apoptosis in human BJAB cells.
abstract: Apoptosis involves the cessation of cellular processes, the breakdown of intracellular organelles, and, finally, the nonphlogistic clearance of apoptotic cells from the body. Important for these events is a family of proteases, caspases, which are activated by a proteolytic cleavage cascade and drive apoptosis by targeting key proteins within the cell. Here, we demonstrate that serum response factor (SRF), a transcription factor essential for proliferative gene expression, is cleaved by caspases and that this cleavage occurs 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 occurs 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 that it correlates with the loss of c-fos expression, whereby neither SRF cleavage fragment retains transcriptional activity. Moreover, the expression of a noncleavable SRF in BJAB cells suppresses apoptosis induced by Fas cross-linking. These results suggest that for apoptosis to proceed, the transcriptional events promoting cell survival and proliferation, in which SRF is involved, must first be inactivated.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom.
authors.forename: V
authors.initials: V
authors.lastname: Drewett
authors.forename: A
authors.initials: A
authors.lastname: Devitt
authors.forename: J
authors.initials: J
authors.lastname: Saxton
authors.forename: N
authors.initials: N
authors.lastname: Portman
authors.forename: P
authors.initials: P
authors.lastname: Greaney
authors.forename: N E
authors.initials: NE
authors.lastname: Cheong
authors.forename: T F
authors.initials: TF
authors.lastname: Alnemri
authors.forename: E
authors.initials: E
authors.lastname: Alnemri
authors.forename: P E
authors.initials: PE
authors.lastname: Shaw
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001224:Aspartic Acid / Q000737:chemistry; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D026362:Serum Response Factor; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D011994:Recombinant Proteins; D026362:Serum Response Factor; D001224:Aspartic Acid; D008156:Luciferases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases