title: Induction of apoptosis and activation of NF-kappaB by CD95 require different signalling thresholds.
abstract: Mutations in the death domain of the death receptor CD95 (APO-1/Fas) cause lymphoproliferation and autoimmune disease in both lpr(cg) mice and in patients with autoimmune lymphoproliferative syndrome (ALPS) type Ia. By testing lymphocytes from ALPS type Ia patients, comparing heterozygous with homozygous lpr(cg) 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-kappaB (NF-kappaB) 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-kappaB 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.
authors.affiliation: The Ben May Institute for Cancer Research, University of Chicago, 924 E 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Legembre
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Barnhart
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.forename: Shrijay
authors.initials: S
authors.lastname: Vijayan
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Straus
authors.forename: Jennifer
authors.initials: J
authors.lastname: Puck
authors.forename: Janet K
authors.initials: JK
authors.lastname: Dale
authors.forename: Michael
authors.initials: M
authors.lastname: Lenardo
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Peter
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005091:Exons; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000096:biosynthesis*
chemical_list: D008024:Ligands; D016328:NF-kappa B; D019014:fas Receptor; D015500:Chloramphenicol O-Acetyltransferase