<i>Fas</i>Gene Mutations in the Canale–Smith Syndrome, an Inherited Lymphoproliferative Disorder Associated with Autoimmunity

Drappa, Jörn; Vaishnaw, Akshay; Sullivan, Kathleen E.; Chu, Jia Li; Elkon, Keith B.

doi:10.1056/nejm199611283352204

Cited by 455 publications

(261 citation statements)

References 42 publications

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“…In the present study, we have verified that Fas mRNA is expressed constitutively in normal colonic mucosa, but Fas gene transcription was reduced in the majority of tumours analysed. Losses or rearrangements of chromosomes are common in tumour cells (Popescu, 1994) Fiucci and Ruberti (1994) (RieuxLaucat et al, 1995;Cascino et al, 1996;Drappa et al, 1996) (Xerri et al, 1995). (Wu et al, 1994;Rieux-Laucat et al, 1995), suggesting that Fas signalling can control the growth of cell populations.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement

Butler

Hewett²,

Butler³

et al. 1998

Br J Cancer

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Summary Expression of Fas, an apoptosis-inducing receptor, in colonic epithelium is progressively reduced during malignant transformation. We have examined the human Fas gene for loss of heterozygosity (LOH) and gross rearrangements in colon tumours and matched normal mucosa. Polymerase chain reaction (PCR) primers were designed to span a Dral restriction fragment length polymorphic site in the gene. Heterozygosity was detected in normal DNA samples by PCR amplification of the polymorphic site and restriction enzyme digestion. Thirtyeight of 88 patients (43%) with colon carcinomas were informative for the assay, and LOH was detected in 6 of the 38 (16%) corresponding tumours. Tumours from three patients with LOH did not express detectable Fas mRNA, and Fas expression was reduced or absent in 7 of 11 tumours from informative patients without LOH. Southern blotting of tumour DNA samples was used to detect rearrangement of the Fas gene, but no altered hybridization patterns were observed in 64 tumours analysed. These findings indicate that disruption of the Fas gene is not primarily responsible for the loss of Fas protein expression reported in colon cancer. We have also shown that loss of Fas gene transcription is common in these tumours, which may be due to epigenetic gene silencing.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement

Butler

Hewett²,

Butler³

et al. 1998

Br J Cancer

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“…That is, in addition to the association between genetic defects in Fas or Fas ligand and autoimmunity in mice (40)(41)(42)(43)(44)(45)(46)(47) and humans (48)(49)(50)(51), non-Fas-based abnormalities may play paramount roles in the pathogenesis and/or perpetuation of SLE.…”

Section: Discussionmentioning

confidence: 99%

Impaired nonrestricted cytolytic activity in systemic lupus erythematosus

Stohl

Elliott

et al. 1997

Arthritis & Rheumatism

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Objective. To determine the cytolytic effector pathway involved in impaired generation of nonrestricted cytolytic activity in systemic lupus erythemato- sus (SLE).Methods. Peripheral blood mononuclear cells (PBMC) from normal subjects and SLE patients were stimulated in vitro with anti-CD3 monoclonal antibody (MAb) and interleukin-2 to promote the generation of nonrestricted cytolytic activity. On day 13 of culture, the PBMC were assayed for cytolytic activity against FasDaudi cells and Fas+ Jurkat cells. The effects on cytotoxicity of calcium chelation, antagonist anti-Fas MAb, tumor necrosis factor (TNF) a and P, and ATP were measured. Intracellular perforin expression was determined by intracellular staining, and perforin messenger RNA levels were determined by quantitative competitive reverse transcription-polymerase chain reaction.Results. We demonstrated the existence of a cytolytic pathway that is independent of Fas, TNFa, TNFP, and ATP, but is dependent upon extracellular calcium. Despite its calcium dependence, this pathway is associated with low-to-undetectable levels of perforin.Conclusion. Impaired generation of nonrestricted ~-cytolytic activity in SLE is likely due to decreased activity of this Fas-, TNFa-, TNFP-, ATP-independent pathway associated with very low levels of perforin.

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“…The cognate ligand for Fas (FasL) is an activation antigen expressed by CD4+ Th1 effector cells and CD8 cytotoxic T lymphocytes, (although its activity in the latter is frequently masked by the more substantial destructive power of the perforin-granzyme system), as well as natural killer cells [8][9][10][11][12][13]. The congenital loss of Fas (as in lpr/lpr mice and Fas null mice, and in human Autoimmune Lymphoproliferation Syndrome) or of its ligand (as in gld/gld mice) is accompanied by severely elevated levels of serum autoantibodies associated with frank autoimmunity [14][15][16][17][18][19][20][21][22][23][24]; for this reason Fas is thought to play a key role in the regulation of B cells, particularly in the regulation of autoreactive B cells. These observations are supported and refined by additional experiments, carried out over the last dozen years, that more clearly document abnormal B cell function in Fas-deficient animals and distinguish B cell defects from abnormalities in the T cell population.…”

Section: Inroductionmentioning

confidence: 99%

Inducible resistance to Fas-mediated apoptosis in B cells

Rothstein

2000

Cell Res

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Apoptosis produced in B cells through Fas (APO-1, CD95) triggering is regulated by signals derived from other surface receptors: CD40 engagement produces upregulation of Fas expression and marked susceptibility to Fas-induced cell death, whereas antigen receptor engagement, or IL-4R engagement, inhibits Fas killing and in so doing induces a state of Fas-resistance, even in otherwise sensitive, CD40-stimulated targets. Surface immunoglobulin and IL-4R utilize at least partially distinct pathways to produce Fas-resistance that differentially depend on PKC and STAT6, respectively. Further, surface immunoglobulin signaling for inducible Fas-resistance bypasses Btk, requires NF-κB, and entails new macromolecular synthesis. Terminal effectors of B cell Fas-resistance include the known anti-apoptotic gene products, Bcl-xL and FLIP, and a novel anti-apoptotic gene that encodes FAIM (Fas Apoptosis Inhibitory Molecule). faim was identified by differential display and exists in two alter-

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FasGene Mutations in the Canale–Smith Syndrome, an Inherited Lymphoproliferative Disorder Associated with Autoimmunity

Abstract: 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.

Cited by 455 publications

References 42 publications

Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement

Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement

Impaired nonrestricted cytolytic activity in systemic lupus erythematosus

Inducible resistance to Fas-mediated apoptosis in B cells

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