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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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Journal ArticleDOI
TL;DR: In this paper , the authors characterized CD95 and CD95L expression in human glioma-initiating cells (GIC), a glioblastoma cell population with stem cell features, and investigated the consequences of CRISPR-Cas9-mediated CD95 or CD95l gene deletion.
Abstract: Abstract CD95 (Fas/APO-1) is a multifunctional cell surface receptor with antithetic roles. First described to mediate cell death, interactions of CD95 with its natural ligand, CD95L, have also been described to induce tumor-promoting signaling leading to proliferation, invasion and stem cell maintenance, mainly in cancer cells that are resistant to CD95-mediated apoptosis. While activation of CD95-mediated apoptosis in cancer cells may not be clinically practicable due to toxicity, inhibition of tumor-promoting CD95 signaling holds therapeutic potential. In the present study, we characterized CD95 and CD95L expression in human glioma-initiating cells (GIC), a glioblastoma cell population with stem cell features, and investigated the consequences of CRISPR-Cas9-mediated CD95 or CD95L gene deletion. In vitro, GIC expressed CD95 but not CD95L and were sensitive to CD95-mediated apoptosis. Upon genetic deletion of CD95 , GIC acquired resistance to CD95L-induced apoptosis but exhibited inferior clonogenic growth, sphere-forming capacity, and invasiveness compared with control cells, suggesting the existence of CD95L-independent constitutive CD95 signaling with tumor-promoting properties in GIC. In vivo, GIC expressed CD95 and a non-canonical form of CD95L lacking the CD95-binding region. CD95 genetic deletion did not prolong survival in immunocompromised GIC-bearing mice. Altogether, these data indicate that canonical CD95L may not be expressed in human GIC and suggest the existence of a CD95L-independent CD95-signaling pathway that maintains some malignancy traits of GIC. The lack of altered survival of tumor-bearing mice after genetic deletion of CD95 suggests that CD95 signaling is not essential to maintain the growth of human GIC xenografted into the brains of nude mice. The ligand-independent tumor-promoting role of constitutive CD95 in our GIC models in vitro highlights the complexity and challenges associated with targeting CD95 with therapeutic intent.

3 citations

Journal ArticleDOI
TL;DR: This research presents a novel probabilistic approach to estimating the response of the immune system to laser-spot assisted, 3D image recognition technology.
Abstract: [This corrects the article DOI: 10.1371/journal.pbio.1001090.].

2 citations

Dissertation
01 Jan 2012
TL;DR: The results showed that, in addition to its proapoptotic effect, the FAS receptor is a crucial regulator of activation and proliferation in activated/memory T cells generated after repeated stimulation by an antigen with low affinity for the TCR (T cell receptor).
Abstract: The extraordinary capacity of the immune system to prevent responses elicited by self antigens is known as self tolerance, and is essential for the maintenance of immune homeostasis. The processes of T cell activation, proliferation and cell death must be precisely regulated to avoid the development of autoimmune diseases such as systemic lupus erythematosus or autoimmune lymphoproliferative syndrome (ALPS). The FAS receptor has classically been associated with a role in apoptosis. Mice with defects in FAS (lpr) and ALPS patients both show a clear loss of tolerance that leads to autoimmunity and development of lymphadenopathy, with marked T cell hyperproliferation of unknown origin. FAS-dependent activation induced cell death (AICD) was initially considered the basis of the lpr mouse phenotype. Nevertheless, although the role of FAS-mediated cell death is well established in vitro, its relevance in apoptosis induction in vivo is debated. Defective apoptosis alone does not account for accumulation of activated T cells; clear evidence is derived from the analysis of mice deficient in other molecules involved in the FAS-activated apoptotic pathway, such as FADD (FAS Associated Death Domain) or C-8 (caspase-8). These mice lack T cell apoptosis but, unlike lpr mice, develop neither autoimmune disease nor lymphadenopathy but are affected by immunodeficiency. This suggests that, in addition to apoptosis, FAS might have other functions in homeostasis control. Since lpr T cells hyperproliferate in vivo and their apoptotic defects are nonetheless insufficient to justify the lymphadenopathy and autoimmunity observed in these mice, we explored the relationship between loss of tolerance and the excessive proliferation of autoreactive T cells in lpr mice. Our results showed that, in addition to its proapoptotic effect, the FAS receptor is a crucial regulator of activation (NF-kB, ERK- 1/2, pro-inflamatory cytokines) and proliferation in activated/memory T cells generated after repeated stimulation by an antigen with low affinity for the TCR (T cell receptor). We have described p21 as a suppressor of autoimmunity, shown by its implication in the control of apoptosis-surviving T cell proliferation after secondary antigen challenge. This led us to speculate that p21 overexpression in lpr mice might reduce the autoimmune disorder, since their T cells hyperproliferate after restimulation. Our data indicate that a reduction in memory T cell proliferation, mediated by T cell-directed p21 overexpression, efficiently reduces lymphadenopathy and disease manifestations in lprp21tg mice. In accordance with these results, lpr-p21-/- mice showed excessive memory T cell activation/ proliferation, leading to severe autoimmune disease and an increased early mortality rate compared to lpr mice. T cell hyperproliferation thus has evident physiological relevance in autoimmunity development in FAS-deficient mice. We propose that both FAS and p21 have an essential function in tolerance establishment, mediated by their functions as negative regulators of memory T cell activation/proliferation.

2 citations


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

  • ...Anteriormente, se ha descrito que la estimulación de FAS conlleva la activación de las rutas de las MAPK y de NF-kB en diferentes procesos relacionados con el crecimiento de neuritas [151], progresión de tumores [152], en progenitores de células del sistema nervioso [153], o en linfocitos de pacientes con ALPS y esplenocitos de ratones lpr/gld [154]....

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  • ...Concretamente, en el trabajo realizado con ratones lpr [154], se analizó la activación de NF-kB en esplenocitos tratados con FAS-L tras una estimulación incompleta con anti-CD3 y una breve expansión con IL-2....

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Journal ArticleDOI
TL;DR: In this paper, the authors found that the number of mesenchymal stem cells significantly increased in tumour-burdened mice driven by Fas-threshold signalling, and that CCL2 and IL6 were induced by pancreatic cancer cell-derived IL1.

2 citations

Dissertation
07 Jun 2017

2 citations


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

  • ...In these cells, it was shown that CD95L treatment triggers the activation of non-apoptotic kinase pathways such as NFκB and MAPK pathways (Barnhart et al., 2004; Legembre et al., 2004a, 2004b)....

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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.

1,472 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)....

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Journal ArticleDOI
02 Jun 1995-Science
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.
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.

1,193 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.

1,096 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.

693 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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