Induction of apoptosis and activation of NF-κB by CD95 require different signalling thresholds
Patrick Legembre,Bryan C. Barnhart,Lixin Zheng,Shrijay Vijayan,Sharon E. Straus,Jennifer M. Puck,Janet K. Dale,Michael J. Lenardo,Marcus E. Peter +8 more
TLDR
It is demonstrated that induction of apoptosis requires two wild‐type alleles 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.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-κB (NF-κB) 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-κB 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.read more
Citations
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Journal ArticleDOI
Transplanted islets from lpr mice are resistant to autoimmune destruction in a model of streptozotocin-induced type I diabetes.
TL;DR: This work has used an alternative model of autoimmune diabetes triggered by repeated low doses of streptozotocin to provide strong support for a major role of CD95 in the destruction of islets in autoimmune mice.
Book ChapterDOI
The Death Receptor Pathway
TL;DR: This chapter provides an updated overview on the signaling pathways mediated by the death receptors and on their role in human physiology and pathophysiology.
Book ChapterDOI
Study of the CD95-Mediated Non-apoptotic Signaling Pathway: PI3K.
Amélie Fouqué,Patrick Legembre +1 more
TL;DR: This chapter demonstrates that CD95 implements the PI3K signaling pathway through the formation of a molecular complex designated Motility Inducing Signaling Complex (MISC) contributing to cell survival, growth, proliferation, differentiation and motility.
Journal ArticleDOI
Fas Mediates Cardiac Allograft Acceptance in Mice with Impaired T Cell-Intrinsic NF-κB Signaling
TL;DR: Results indicate that T‐cell inhibition of NF‐κB results in cardiac allograft acceptance because of increased susceptibility to Fas‐mediated cell death.
Journal ArticleDOI
Mice lacking functional CD95-ligand display reduced proliferation of the intestinal epithelium without gross homeostatic alterations
Kari Trumpi,Ernst J.A. Steller,Wendy W.J. de Leng,Danielle A.E. Raats,Isaac J Nijman,Folkert H.M. Morsink,Inne H.M. Borel Rinkes,Onno Kranenburg +7 more
TL;DR: It is concluded that CD95L has a proliferation-stimulating role during normal turnover of the small intestine, but has a marginal effect on overall intestinal homeostasis.
References
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Journal ArticleDOI
Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome
Galen H. Fisher,Fredric J Rosenberg,Sharon E. Straus,Janet K. Dale,Lindsay A. Middelton,Albert Y. Lin,Warren Strober,Michael J. Lenardo,Jennifer M. Puck +8 more
TL;DR: The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of lymphocyte homeostasis and peripheral self-tolerance.
Mutations inFasAssociated withHuman Lymphoproliferative Syndrome and Autoimmunity
P. Lane,M. Lohoff,F. Rieux-Laucat,F. LeDeist,C. Hivroz,A. G. Roberts,K. M. Debatin,A. Fischer +7 more
TL;DR: Fas expression and function were analyzed in three children with a lymphoproliferative syndrome and may provide a molecular basis for some autoimmune diseases in humans.
Journal ArticleDOI
Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity
Frédéric Rieux-Laucat,F. Le Deist,C Hivroz,Irene Roberts,Klaus-Michael Debatin,Alain Fischer,J P de Villartay +6 more
TL;DR: Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders as discussed by the authors, showing that a large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient.
Journal ArticleDOI
The CD95(APO-1/Fas) DISC and beyond
Marcus E. Peter,Peter H. Krammer +1 more
TL;DR: A number of proteins have been reported to regulate formation or activity of the DISC, the complex of proteins that forms upon triggering of CD95 that is essential for induction of apoptosis.
Journal ArticleDOI
Fas Preassociation Required for Apoptosis Signaling and Dominant Inhibition by Pathogenic Mutations
Richard M. Siegel,John K. Frederiksen,David A. Zacharias,Francis Ka-Ming Chan,Michele M. Johnson,David A. Lynch,Roger Y. Tsien,Michael J. Lenardo +7 more
TL;DR: Results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.