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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.
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.

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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.

591 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.

578 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 ...

406 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).

279 citations

References
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Journal ArticleDOI
TL;DR: Patients with the Canale-Smith syndrome have mutations in Fas, which implicates this gene in the accumulation of lymphocytes and the autoimmunity characteristic of the syndrome.
Abstract: Background The Canale–Smith syndrome is a childhood disorder characterized by lymphadenopathy and autoimmunity. The similarity between this syndrome and that in mice with the lymphoproliferation (lpr ) phenotype or the generalized-lymphoproliferative-disease (gld) phenotype led us to investigate whether it too is caused by mutations of the Fas gene (lpr mice) or the Fas ligand (gld mice), which regulate apoptosis in lymphocytes. Methods We studied four patients with the syndrome and their families. T-lymphocyte phenotypes were analyzed, and the susceptibility of activated T cells to Fas-mediated apoptosis in vitro was determined. Mutations of Fas were sought by nucleotide-sequence analysis. Results Patients with the Canale–Smith syndrome had increased numbers of circulating double-negative T cells (>20 percent) and profoundly impaired apoptosis of activated T cells incubated with an anti-Fas antibody. Three novel Fas mutations were identified, all of which were heterozygous and predicted to impair signal ...

481 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)....

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Journal ArticleDOI
01 Jul 2001-Blood
TL;DR: Investigation of 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS, implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas.

435 citations

Journal ArticleDOI
TL;DR: The transcription factor NF-kappaB is a key regulator in oncogenesis by promoting proliferation and inhibiting apoptosis, which tips the balance between proliferation and apoptosis toward malignant growth in tumor cells.

348 citations


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

  • ...Activation of NF-kB promotes tumour growth through transcriptional activation of a number of target genes that exert proliferative, antiapoptotic and/or tumorigenic functions (Lin & Karin, 2003)....

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Journal ArticleDOI
TL;DR: It is reported that crosslinking Fas on primary sensory neurons induces neurite growth through sustained activation of the extracellular-signal regulated kinase (ERK) pathway and the consequent upregulation of p35, a mediator of neurite outgrowth.
Abstract: Fas (also known as CD95), a member of the tumour-necrosis receptor factor family of 'death receptors', can induce apoptosis or, conversely, can deliver growth stimulatory signals. Here we report that crosslinking Fas on primary sensory neurons induces neurite growth through sustained activation of the extracellular-signal regulated kinase (ERK) pathway and the consequent upregulation of p35, a mediator of neurite outgrowth. In addition, functional recovery after sciatic nerve injury is delayed in Fas-deficient lpr mice and accelerated by local administration of antibodies against Fas, which indicates that Fas engagement may contribute to nerve regeneration in vivo. Our findings define a role for Fas as an inducer of both neurite growth in vitro and accelerated recovery after nerve injury in vivo.

322 citations


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

  • ...Our findings on the lack of activation of Erk1/2 in cells expressing two CD95 mutant alleles differ from those in a study that reported that in certain neurons from lprcg/lprcg mice, triggering of CD95 can still activate Erk1/2 (Desbarats et al, 2003)....

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  • ...Using an enzyme-linked immunosorbent assay (ELISA) specific for p65, EMSA and western blot analysis, we documented the activation of NF-kB, Erk1/2 and p38 in cells from both wild-type and wt/lprcg mice, but not in cells from lprcg/lprcg mice (Fig 3B,C and supplementary Fig 2A online)....

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  • ...We now demonstrate that cells carrying heterozygous mutations in the CD95 DD are deficient in induction of apoptosis but can still efficiently activate the transcription factor NF-kB and the MAP kinases Erk1/2 and p38....

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  • ...In addition to serving a critical role in mediating lymphocyte apoptosis, stimulation of CD95 has been shown to result in activation of the transcription factor nuclear factor-kB (NF-kB) and of mitogen-activated protein (MAP) kinases (Desbarats et al, 2003; Wajant et al, 2003)....

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Journal ArticleDOI
24 Sep 1992-Nature
TL;DR: It is demonstrated that Bcl-3 can aid κB site-dependent transcription in vivo by counteracting the inhibitory effects of p50/NF-κB homodimers, and may therefore aid activation of select NF-κBs-regulated genes, including those of the human immunodeficiency virus.
Abstract: The candidate oncogene bcl-3 was discovered as a translocation into the immunoglobulin alpha-locus in some cases of B-cell chronic lymphocytic leukaemias. The protein Bcl-3 contains seven so-called ankyrin repeats. Similar repeat motifs are found in a number of diverse regulatory proteins but the motifs of Bcl-3 are most closely related to those found in I kappa B proteins in which the ankyrin repeat domain is thought to be directly involved in inhibition of NF-kappa B activity. No biological function has yet been described for Bcl-3, but it was noted recently that Bcl-3 interferes with DNA-binding of the p50 subunit of NF-kappa B in vitro. Here we demonstrate that Bcl-3 can aid kappa B site-dependent transcription in vivo by counteracting the inhibitory effects of p50/NF-kappa B homodimers. Bcl-3 may therefore aid activation of select NF-kappa B-regulated genes, including those of the human immunodeficiency virus.

309 citations


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

  • ...MCF-7 cells were transfected with an HIV-kB-CAT reporter plasmid driven by the kB sites in the HIV LTR (Franzoso et al, 1992) using Polyfect from Qiagen (Maryland, USA) according to the manufacturer’s protocols....

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