Cleavage of the serum response factor during death receptor-induced apoptosis results in an inhibition of the c-FOS promoter transcriptional activity.
The c-FOS protooncogene is rapidly induced by a wide variety of extracellular stimuli including mitogenic signals. Regulation of c-FOS expression is tightly dependent on the serum response element localized within its promoter. Two transcription factors, the serum response factor (SRF) and the ternary complex factor, bind to the serum response element and play a key role in the regulation of the c-FOS promoter activity. In the present study, we show that two death effectors (CH11 and TRAIL) severely impaired the transcriptional activity of the c-FOS promoter in Jurkat T cells. This inhibition can be accounted for by the specific cleavage by caspase 3 of the SRF both in vitro and in vivo, since acetyl-DEVD-aldehyde prevented SRF cleavage and abolished the inhibitory effect of CH11 and TRAIL on the c-FOS promoter activity. Moreover, phorbol myristate acetate, a potent anti-apoptotic effector, was found to protect SRF completely from cleavage by caspase 3 and also to prevent the inhibition of the c-FOS promoter activity by death effectors. Survival factors play an essential function in the regulation of cell growth mainly by regulating the expression of immediate early gene such as c-FOS. In this line, cleavage of SRF at the onset of apoptosis could abrogate the ability of the cell to induce inappropriate survival pathways. All together, our results are consistent with a role of SRF at the interface between cell survival and death pathways.
Bertolotto
C
C
INSERM U526, Activation des Cellules Hématopoïétiques, Physiopathologie de la Survie et de la Mort Cellulaires et Infections Virales, Faculté de Médecine, 28 Avenue de Valombrose, 06107 Nice Cedex 2, France.
Ricci
J E
JE
Luciano
F
F
Mari
B
B
Chambard
J C
JC
Auberger
P
P
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D016762:Genes, fos / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D026362:Serum Response Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D018124:Receptors, Tumor Necrosis Factor; D026362:Serum Response Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate