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
Targeting the Fas/Fas ligand pathway in cancer
Darren I. O'Brien,Kenneth Nally,Raymond Kelly,Terrence M O'Connor,Fergus Shanahan,Joe O'Connell +5 more
TL;DR: This review summarises the current understanding of the Fas/FasL system in tumorigenesis and discusses attempts to utilise the Fas /Fas L system in the treatment of cancer.
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Many checkpoints on the road to cell death: regulation of Fas-FasL interactions and Fas signaling in peripheral immune responses
TL;DR: Harnessing the apoptosis-inducing potential of Fas for therapy of cancer and autoimmune disease has been actively pursued, and despite a number of unexpected side-effects that result from manipulating Fas-FasL interactions, this remains a worthy goal.
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Rewinding the DISC
TL;DR: Fas (CD95/APO-1) belongs to the tumor necrosis factor receptor family and its signaling pathway has been extensively studied over the past 15 years, with mixed results.
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The immunosuppressor mycophenolic acid kills activated lymphocytes by inducing a nonclassical actin-dependent necrotic signal.
Benjamin Chaigne-Delalande,Gwendaline Guidicelli,Lionel Couzi,Pierre Merville,Walid Mahfouf,Walid Mahfouf,Stéphane Bouchet,Stéphane Bouchet,Mathieu Molimard,Mathieu Molimard,Benoît Pinson,Benoît Pinson,Jean-François Moreau,Patrick Legembre,Patrick Legembre +14 more
TL;DR: It is shown that in contrast to the immunosuppressors azathioprine, cyclosporin A, and tacrolimus, MPA killed lymphocytes through the activation of a caspase-independent necrotic signal, which relied on the transmission of a novel intracellular signal involving Rho-GTPase Cdc42 activity and actin polymerization.
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Fas ligand promotes tumor immune evasion of colon cancer in vivo.
TL;DR: It is indicated that upregulation of FasL expression by colon tumor cells results in an improved anti-tumor immune challenge in vivo, providing functional evidence in favor of the ‘Fas counterattack’ as a mechanism of tumor immune evasion.
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.