CD95/Fas signaling in T lymphocytes induces the cell cycle control protein p21cip-1/WAF-1, which promotes apoptosis

Ligation of CD95 on T lymphocytes resulted in the up-regulation of a cell cycle control protein, p2(cip-1/WAF-1), an inhibitor of cyclin-dependent kinases, This up-regulation was completely blocked by the cysteine protease inhibitor Z-VAD-fmk (benzyloxy-carbonyl:Val-Ala-Asp-fluoromethylketone), whereas DEVD-CHO (succinyl-Asp Glu-Val-Asp-aldehyde), a caspase 3 inhibitor, had no effect. In Fas(lpr-cg) mice, a point mutation in the death domain of CD95 results in failure to recruit FADD (Fas-associated death domain), and in the present study this mutation prevented both CD95-mediated apoptosis and p21(cip-1/WAF-1) induction. During apoptotic cell death due to irradiation, p21(cip-1/WAF-1) is, up-regulated by a p53-dependent pathway that responds to DNA damage. However, CD95-induced up-regulation of p21(cip-1/WAF-1) in T cells was p53-independent, T cells deficient in p2(cip-1/WAF-1) were less susceptible to CD95-induced. apoptosis, We conclude that in T cells, ligation of CD95 and activation of caspases cause the induction of p21(cip-1/WAF-1), which acts to promote cell death.