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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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.
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Life and death in peripheral T cells
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Hepatocyte Death: A Clear and Present Danger
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cFLIP regulation of lymphocyte activation and development
TL;DR: Insight gained from studies indicates that cFLIP and caspase-8 form a heterodimer that ultimately links T-cell-receptor signalling to activation of nuclear factor-κB through a complex that includes B-cell lymphoma 10 (BCL-10), mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1) and receptor-interacting protein 1 (RIP1).
References
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Journal ArticleDOI
CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells.
Bryan C. Barnhart,Patrick Legembre,Eric M. Pietras,Concetta Bubici,Guido Franzoso,Marcus E. Peter +5 more
TL;DR: The data suggest that CD95L, which is found elevated in many human cancer patients, has tumorigenic activities on human cancer cells, and could become highly relevant during chemotherapy, which can cause upregulation of CD95 ligand by both tumor and nontumor cells.
Journal ArticleDOI
Non-apoptotic Fas signaling.
TL;DR: The similarities and differences of the molecular mechanisms of apoptotic and non-apoptotic Fas signaling are addressed and the pathways that are utilized by Fas to transduce proliferative and activating signals are poorly understood.
Journal ArticleDOI
Pathological Findings in Human Autoimmune Lymphoproliferative Syndrome
Megan S. Lim,Sharon E. Straus,Janet K. Dale,Thomas A. Fleisher,Maryalice Stetler-Stevenson,Warren Strober,Michael C. Sneller,Jennifer M. Puck,Michael J. Lenardo,Kojo S.J. Elenitoba-Johnson,Albert Y. Lin,Mark Raffeld,Elaine S. Jaffe +12 more
TL;DR: Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS.
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Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.
David A. Martin,Lixin Zheng,Richard M. Siegel,Baohua Huang,Galen H. Fisher,Jin Wang,Christine E. Jackson,Jennifer M. Puck,Janet K. Dale,Sharon E. Straus,Marcus E. Peter,Peter H. Krammer,Stephen W. Fesik,Michael J. Lenardo +13 more
TL;DR: It is suggested that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.
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Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death-inducing signaling complex
Marcus E. Peter,Frank C. Kischkel,C Scheuerpflug,Jan Paul Medema,Klaus-Michael Debatin,Peter H. Krammer +5 more
TL;DR: The experiments presented suggest that resistance to CD95‐mediated apoptosis in T cells can also be regulated at the level of recruitment of FLICE to the DISC.