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Journal ArticleDOI

Induction of apoptosis and activation of NF-κB by CD95 require different signalling thresholds

01 Nov 2004-EMBO Reports (John Wiley & Sons, Ltd)-Vol. 5, Iss: 11, pp 1084-1089

TL;DR: 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.

AbstractMutations 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.

Topics: Autoimmune lymphoproliferative syndrome (56%), Fas receptor (55%), Death domain (51%), Apoptosis (51%)

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Citations
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01 Jan 1995
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.
Abstract: Fas (also known as Apo1 and CD95) is a cell surface receptor involved in apoptotic cell death. Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders. A large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient. Clinical manifestations in the two related patients were less severe: Fas-mediated apoptosis was impaired and a deletion within the intracytoplasmic domain was detected. These findings illustrate the crucial regulatory role of Fas and may provide a molecular basis for some autoimmune diseases in humans.

1,194 citations


Journal ArticleDOI
TL;DR: The concepts of activation-induced cell death (AICD) and activated cell-autonomous death (ACAD) in the regulation of life and death in T cells are discussed.
Abstract: During the course of an immune response, antigen-reactive T cells clonally expand and then are removed by apoptosis to maintain immune homeostasis. Life and death of T cells is determined by multiple factors, such as T-cell receptor triggering, co-stimulation or cytokine signalling, and by molecules, such as caspase-8 (FLICE)-like inhibitory protein (FLIP) and haematopoietic progenitor kinase 1 (HPK1), which regulate the nuclear factor-kappaB (NF-kappaB) pathway. Here, we discuss the concepts of activation-induced cell death (AICD) and activated cell-autonomous death (ACAD) in the regulation of life and death in T cells.

563 citations


Journal ArticleDOI
TL;DR: Insights into these various death receptor signaling pathways provide new therapeutic strategies targeting these receptors in pathophysiological processes, including regulation of cell proliferation and differentiation, chemokine production, inflammatory responses, and tumor‐promoting activities.
Abstract: Death receptors are members of the tumor necrosis factor receptor superfamily characterized by a cytoplasmic region known as the “death domain” that enables the receptors to initiate cytotoxic signals when engaged by cognate ligands. Binding to the ligand results in receptor aggregation and recruitment of adaptor proteins, which, in turn, initiates a proteolytic cascade by recruiting and activating initiator caspases 8 and 10. Death receptors were once thought to primarily induce cytotoxic signaling cascades. However, recent data indicate that they initiate multiple signaling pathways, unveiling a number of nonapoptosis-related functions, including regulation of cell proliferation and differentiation, chemokine production, inflammatory responses, and tumor-promoting activities. These noncytotoxic cascades are not simply a manifestation of inhibiting proapoptotic pathways but are intrinsically regulated by adaptor protein and receptor internalization processes. Insights into these various death receptor signaling pathways provide new therapeutic strategies targeting these receptors in pathophysiological processes.—Guicciardi, M. E., Gores, G. J. Life and death by death receptors.

509 citations


Cites background from "Induction of apoptosis and activati..."

  • ...In contrast, the signaling threshold to activate NF- B is significantly lower and can be achieved even in the presence of only one functional Fas allele (74)....

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  • ...This advantage is likely due to the fact that Fas-induced apoptosis requires two functional Fas alleles in order to ensure efficient DISC formation (74)....

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Journal ArticleDOI
TL;DR: The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in the enterohepatic circulation of bile acids, and the widespread prevalence of hepatotropic viruses.
Abstract: The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in ...

376 citations


Cites background from "Induction of apoptosis and activati..."

  • ...This advantage could be explained by the evidence that Fas-induced apoptosis requires two functional Fas alleles to ensure efficient DISC formation, whereas, in contrast, only one functional allele is sufficient to activate NF- B and promote cell survival (158)....

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Journal ArticleDOI
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).
Abstract: Cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) was originally identified as an inhibitor of death-receptor signalling through competition with caspase-8 for recruitment to FAS-associated via death domain (FADD). More recently, it has been determined that both cFLIP and caspase-8 are required for the survival and proliferation of T cells following T-cell-receptor stimulation. This paradoxical finding launched new investigations of how these molecules might connect with signalling pathways that link to cell survival and growth following antigen-receptor activation. As discussed in this Review, insight gained from these studies indicates that cFLIP and caspase-8 form a heterodimer that ultimately links T-cell-receptor signalling to activation of nuclear factor-kappaB 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).

263 citations


References
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Journal ArticleDOI
16 Jun 1995-Cell
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.
Abstract: Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+CD4-CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child had defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. 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.

1,438 citations


"Induction of apoptosis and activati..." refers background in this paper

  • ...Mutations in the DD have been shown to abrogate induction of apoptosis (Fisher et al, 1995)....

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01 Jan 1995
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.
Abstract: Fas (also known as Apo1 and CD95) is a cell surface receptor involved in apoptotic cell death. Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders. A large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient. Clinical manifestations in the two related patients were less severe: Fas-mediated apoptosis was impaired and a deletion within the intracytoplasmic domain was detected. These findings illustrate the crucial regulatory role of Fas and may provide a molecular basis for some autoimmune diseases in humans.

1,194 citations


"Induction of apoptosis and activati..." refers background in this paper

  • ...Mutations in the DD of CD95 are naturally found both in mice (lprcg mice; Kimura & Matsuzawa, 1994) and in many patients suffering from autoimmune lymphoproliferative syndrome (ALPS) type Ia (Rieux-Laucat et al, 1995, 1999; Drappa et al, 1996; Martin et al, 1999; Straus et al, 2001)....

    [...]


Journal ArticleDOI
02 Jun 1995-Science
Abstract: Fas (also known as Apo1 and CD95) is a cell surface receptor involved in apoptotic cell death. Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders. A large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient. Clinical manifestations in the two related patients were less severe: Fas-mediated apoptosis was impaired and a deletion within the intracytoplasmic domain was detected. These findings illustrate the crucial regulatory role of Fas and may provide a molecular basis for some autoimmune diseases in humans.

1,163 citations


Journal ArticleDOI
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.
Abstract: CD95 (APO-1/Fas) is a prototype death receptor characterized by the presence of an 80 amino acid death domain in its cytoplasmic tail. This domain is essential for the recruitment of a number of signaling components upon activation by either agonistic anti-CD95 antibodies or cognate CD95 ligand that initiate apoptosis. The complex of proteins that forms upon triggering of CD95 is called the death-inducting signaling complex (DISC). The DISC consists of an adaptor protein and initiator caspases and is essential for induction of apoptosis. A number of proteins have been reported to regulate formation or activity of the DISC. This review discusses recent developments in this area of death receptor research.

1,071 citations


"Induction of apoptosis and activati..." refers background in this paper

  • ...On binding of CD95 ligand (CD95L), CD95 recruits the adaptor protein FADD, the initiator caspases 8 and 10 and the apoptosis regulator c-FLIP, forming the death-inducing signalling complex (DISC; Peter & Krammer, 2003)....

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Journal ArticleDOI
30 Jun 2000-Science
TL;DR: Results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.
Abstract: Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced lymphocyte apoptosis in human autoimmune lymphoproliferative syndrome. This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand- independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein. These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.

669 citations


"Induction of apoptosis and activati..." refers background in this paper

  • ...&2004 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION EMBO reports VOL 5 | NO 11 | 2004 scientificreport 1085 wild-type receptors (Siegel et al, 2000)....

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