Disease relevance of TNFRSF1A

• TNFRSF1A mutations were found in patients of various ethnic origins, including those at risk for familial Mediterranean fever (FMF): Armenians, Sephardic Jews, and especially Arabs from Maghreb. Only 3 (10.7%) of the 28 patients had amyloidosis [1].
• This syndrome is an autosomal dominant disorder characterized by recurring episodes of fever, arthralgia, and skin lesions that is caused by mutations in the 55-kd TNFRSF1A gene [2].
• CONCLUSIONS: We report a novel mutation (C55S) in TNFRSF1A, resulting in autosomal-dominant periodic fever and AA amyloidosis [3].
• Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: a prospective, randomized, placebo- and drug-controlled study [4].
• The TNFRSF1A gene was screened for polymorphisms in 95 subjects with premature myocardial infarction (MI), who also had one parent who had an MI [5].

Psychiatry related information on TNFRSF1A

• Neither the polymorphism in the TNFR1 nor that in the TNFR2 gene was associated with narcolepsy [6].
• (3) Fetuses of patients who delivered within 72 hours of cordocentesis had significantly higher concentrations of TNF-R1 and TNF-R2 receptors than those with longer latency periods (P<.05 for each) [7].
• Measurements of the soluble TNF receptor (sTNF-R) concentrations in healthy individuals at time lapses of 3 months (17 individuals) or 1 year (51 individuals) showed a significant correlation between the first and the second measurements from each individual, implying that individual differences are stable [8].
• The results of these studies establish a new role for myosin II motor activity in regulating TNFR-1-mediated apoptosis through the translocation of TNFR-1 to or within the plasma membrane [9].

High impact information on TNFRSF1A

• TNF and TNFR family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs [10].
• Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex [11].
• TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival [11].
• We report that TNFR1-induced apoptosis involves two sequential signaling complexes [11].
• We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor [12].

Chemical compound and disease context of TNFRSF1A

• Taken together, these results suggest that differences in susceptibility to TNF-alpha-induced apoptosis among MCF-7 breast cancer cell variants may be explained by differences in TNFR expression, ceramide generation, differential expression of the Bcl-2 family of proteins, and protease activation [13].
• Evaluation of soluble tumor necrosis factor (TNF) receptors and TNF receptor antibodies in patients with systemic lupus erythematodes, progressive systemic sclerosis, and mixed connective tissue disease [14].
• BACKGROUND: The contribution of TNF receptor (TNF-R) expression was investigated with respect to TNF sensitivity or insensitivity for androgen-dependent and androgen-independent human prostate cancer (PCA) cell lines, respectively [15].
• Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice [16].
• After adjustment for sex, race-ethnicity, hypertension, diabetes mellitus, LDL cholesterol, smoking, and body mass index, associations remained (mean difference=0.36 mm, P=0.001 for TNF receptor 1 and mean difference=0.09 mm, P=0.051 for TNF receptor 2) [17].

Biological context of TNFRSF1A

• Recently, mutations in the TNFRSF1A gene on chromosome 12p13 encoding tumor necrosis factor receptor type 1 have been linked to this autoinflammatory syndrome [18].
• In two families with dominantly inherited disease and in 90 sporadic cases that presented with a compatible clinical history, we have not identified any TNFRSF1A mutation, despite comprehensive genomic sequencing of all of the exons, therefore suggesting further genetic heterogeneity of the periodic-fever syndromes [19].
• The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers [19].
• CONCLUSION: The C43S TNFRSF1A mutation results in decreased TNFalpha-induced nuclear signaling and apoptosis [20].
• Comparison of these data with other published frequencies of TNFRSF1A and TNFRSF1B genotypes according to race suggests that the distribution in African American, Caucasian, and Asian populations differs significantly [21].

Anatomical context of TNFRSF1A

• Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes [22].
• RESULTS: Activation-induced shedding of the TNFRSF1A from neutrophils was not altered by the C43S TRAPS mutation [20].
• TNFalpha-induced activation of NF-kappaB and AP-1 was decreased in the primary dermal fibroblasts with the C43S TNFRSF1A mutation [20].
• Adipose tissue PAI-1 levels were positively associated with TNFRSF1s and TGFbeta, the strongest relationship being observed with TNFRSF1A, which explained 82% of PAI-1 variability [23].
• In some patients, the pathogenesis involves defective TNFRSF1A shedding from cell membranes in response to a given stimulus [24].

Associations of TNFRSF1A with chemical compounds

• OBJECTIVE: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autoinflammatory syndrome associated with mutations in the gene that encodes tumor necrosis factor receptor superfamily 1A (TNFRSF1A) [20].
• RESULTS: A novel mutation, a heterozygous C to T transition in exon 3 which substitutes an isoleucine for a threonine at position 61 (T61I) was detected in the TNFRSF1A gene derived from the genomic DNA of a Japanese female TRAPS patient [25].
• The extracellular cysteine-rich domain of the TNF-R is homologous to the nerve growth factor receptor and the B cell activation protein Bp50 [26].
• Grb2 binds with its COOH-terminal SH3 domain to a PLAP motif within TNFR-I and with its NH2-terminal SH3 domain to SOS (son of sevenless) [27].
• However, both TNF-R55 and TNF-R75 upregulate alpha 2 integrin expression in HUVEC [28].

Physical interactions of TNFRSF1A

• Human embryonic kidney cells transfected with a TNF-R expression vector specifically bind both 125I-labeled and biotinylated TNF-alpha [26].
• We propose that formation of a TNFR1-ARTS-1 molecular complex represents a novel mechanism by which TNFR1 shedding is regulated [29].
• Interleukin-10-induced HIV-1 expression is mediated by induction of both membrane-bound tumour necrosis factor (TNF)-alpha and TNF receptor type 1 in a promonocytic cell line [30].
• WSL-1 also interacts specifically with the TNFR1-associated molecule TRADD [31].
• Here we report that the cytosolic adapter protein Grb2 is a novel binding partner of TNFR-I [27].

Enzymatic interactions of TNFRSF1A

• In adherent neutrophils, when beta-integrin signaling is activated, TNF phosphorylates TNFR-1 and activates prosurvival and antiapoptotic signaling [32].
• Analysis of in vitro protein phosphorylation in the presence of the active kinase indicates that a 60-kD cytosolic protein (p60) was markedly phosphorylated and served as the major substrate for MAPKAP kinase 2 in human neutrophils [33].

Regulatory relationships of TNFRSF1A

• The TNF-alpha-induced cell adhesion to HUVEC was found to be controlled almost exclusively by TNF-R55 [28].
• The CD44 adhesion molecule in HUVEC was also found to be upregulated through TNF-R55 [28].
• These data indicate that ARTS-1 is a multifunctional ectoprotein capable of binding to and promoting TNFR1 shedding [29].
• In contrast to the TNF-R75 mAb, TNF-R55 mAbs induced down-regulation of TNF-R75 and shedding of both TNF-R55-BP and TNF-R75-BP [34].
• FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis [35].
• Taken together, these results suggest that oxidative stress promotes TNFR receptor self-interaction and ligand-independent and enhanced ligand-dependent TNF signaling [36].

Other interactions of TNFRSF1A

• These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades [37].
• Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory mediator that exerts its biological functions by binding two TNF receptors (TNF-RI and TNF-RII), which initiate biological responses by interacting with adaptor and signalling proteins [38].
• The human receptor for TRAIL was found to be an undescribed member of the TNF-receptor family (designated death receptor-4, DR4) that contains a cytoplasmic "death domain" capable of engaging the cell suicide apparatus but not the nuclear factor kappa B pathway in the system studied [39].
• Therefore, SAPK activation occurs through a pathway that is not required for TNF-R1-induced apoptosis [40].
• Evidence that signaling outputs are shaped by intracellular constraints helps reconcile conflicting views of TNFR1 and TNFR2 as apoptotic mediators [41].

Analytical, diagnostic and therapeutic context of TNFRSF1A

• In view of the possibility of TRAPS, sequence analysis of the TNFRSF1A gene was also performed [18].
• METHODS: TNFRSF1A shedding from neutrophils was measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA) [20].
• Membrane TNFRSF1A expression was analysed on the surface of peripheral blood mononuclear cells by flow cytometry [25].
• DNA was isolated from patient blood samples and subsequently used to genotype both the exon 1 TNFRSF1A SNP and the exon 6 TNFRSF1B SNP by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis [42].
• Consistent with this, WT and mutant full-length TNFRSF1A formed cytoplasmic aggregates that co-localized with ubiquitin and chaperones, and with the signal transducer TRADD, but not with the inhibitor, silencer of death domain (SODD) [43].

References