title: CD95 (Fas)-induced caspase-mediated proteolysis of NF-kappaB.
abstract: Activation of the nuclear factor (NF)-kappaB transcription factor is instrumental for the immune response and the survival of peripheral activated T cells. We demonstrate that ligation of CD95 (Fas/APO1), a potent apoptotic stimulus in lymphocytes, results in repression of NF-kappaB activity in Jurkat T cells by inducing the proteolytic cleavage of NF-kappaB p65 (Rel A) and p50. Inhibition of caspase-3-related proteases by a specific acetylated aldehyde (Ac-DEVD-CHO) prevented CD95-induced cleavage of p65 (RelA) or p50 and restored the inducibility of NF-kappaB in cells treated with an antibody against CD95. The addition of recombinant caspase-3 also resulted in proteolytic cleavage of RelA p65 and p50 in vitro. TNF-alpha treatment, unlike CD95 ligation, did not result in the death of Jurkat cells but did so in the presence of I kappaB alphaM, a transdominant inhibitor of NF-kappaB. These results suggest that intact, functional NF-kappaB maintains the survival of activated T cells, and that CD95-induced cleavage of NF-kappaB subunits sensitizes T cells to apoptosis and, hence, facilitates the decay of an immune response.
authors.affiliation: Johns Hopkins Oncology Center, Division of Experimental Therapeutics and Pharmacology, Baltimore, Maryland 21287, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ravi
authors.forename: A
authors.initials: A
authors.lastname: Bedi
authors.forename: E J
authors.initials: EJ
authors.lastname: Fuchs
authors.forename: A
authors.initials: A
authors.lastname: Bedi
mesh_terms: D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases