C. Bertolotto et al., Cleavage of the serum response factor during death receptor-induced apoptosis results in an inhibition of the c-FOS promoter transcriptional activity, J BIOL CHEM, 275(17), 2000, pp. 12941-12947
The c-FOS protooncogene is rapidly induced by a wide variety of extracellul
ar stimuli including mitogenic signals. Regulation of c-FOS expression is t
ightly dependent on the serum response element localized within its promote
r. Two transcription factors, the serum response factor (SRF) and the terna
ry complex factor, bind to the serum response element and play a key role i
n the regulation of the c-FOS promoter activity. In the present study, we s
how that two death effecters (CH11 and TRAIL) severely impaired the transcr
iptional 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 ac
tivity. Moreover, phorbol myristate acetate, a potent anti-apoptotic effect
or, 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 effector
s. Survival factors play an essential function in the regulation of cell gr
owth 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 tog
ether, our results are consistent with a role of SRF at the interface betwe
en cell survival and death pathways.