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- Title
Induction of apoptosis and activation of NF-?B by CD95 require different signalling thresholds.
- Authors
Legembre, Patrick; Barnhart, Bryan C.; Zheng, Lixin; Vijayan, Shrijay; Straus, Stephen E.; Puck, Jennifer; Dale, Janet K.; Lenardo, Michael; Peter, Marcus E.
- Abstract
Mutations in the death domain of the death receptor CD95 (APO-1/Fas) cause lymphoproliferation and autoimmune disease in both lprcg mice and in patients with autoimmune lymphoproliferative syndrome (ALPS) type Ia. By testing lymphocytes from ALPS type Ia patients, comparing heterozygous with homozygous lprcg mice and coexpressing wild-type and mutant CD95 receptors, we demonstrate that induction of apoptosis requires two wild-type alleles of CD95. By contrast, nuclear factor-?B (NF-?B) can be fully activated in cells expressing both a mutant and a wild-type CD95 allele, suggesting different thresholds to activate the two signalling pathways. This was confirmed by testing lymphocytes from heterozygous lpr mice, which showed reduced sensitivity to CD95-mediated apoptosis but normal activation of NF-?B when compared with wild-type mice. Mutations in CD95 may eliminate the tumour-suppressive function of CD95, at the same time allowing induction of survival or proliferative pathways, which could contribute to the increased risk for lymphoma seen in ALPS type Ia patients.
- Subjects
GENETIC mutation; APOPTOSIS; LYMPHOCYTES; TUMORS; LYMPHOMAS; PATIENTS
- Publication
EMBO Reports, 2004, Vol 5, Issue 11, p1084
- ISSN
1469-221X
- Publication type
Article
- DOI
10.1038/sj.embor.7400280