Physical Mapping and Genomic Structure of the HumanTNFR2Gene

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104-4318, USA.
Genomics (Impact Factor: 2.28). 07/1996; 35(1):94-100. DOI: 10.1006/geno.1996.0327


The tumor necrosis factor receptor 2 (TNFR2) gene localizes to 1p36. 2, a genomic region characteristically deleted in neuroblastomas and other malignancies. In addition, TNFR2 is the principal mediator of the effects of TNF on cellular immunity, and it may cooperate with TNFR1 in the killing of nonlymphoid cells. Therefore, we undertook an analysis of the genomic structure and precise physical mapping of this gene. The TNFR2 gene is contained on 10 exons that span 26 kb. Most of the functional domains of TNFR2 are encoded by separate exons, and each of the repeats of the extracellular cysteine-rich domain is interrupted by an intron. The genomic structure reveals a close relationship to TNFR1, another member of the TNFR superfamily. Based on electrophoretic analysis of yeast artificial chromosomes, TNFR2 maps within 400 kb of the genetic marker D1S434. In addition, we have identified a new polymorphic dinucleotide repeat within intron 4 of TNFR2. The genetic sequence information and exon-intron boundaries we have determined will facilitate mutational analysis of this gene to determine its potential role in neuroblastoma, as well as in other cancers with characteristic deletions or rearrangements of 1p36.

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    • "The TNFRI gene is located on chromosome 12p13 consisting of 10 exons [17] [18] and contains a housekeeping promoter with multiple transcription start sites, a high GC content, and missing consensus TATA and CAAT box motifs [19]. The TNFRII gene is located on chromosome 1p36 and also contains 10 exons [17] [20], a TNFRII promoter also high in GC content, but containing several consensus TATA box motifs [21]. What impact cytokines have on the nature of the developing immune response depends both on the percentage of cells expressing membrane-bound receptors and on receptor expression levels on respective cells [22]. "
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    ABSTRACT: The level of TNF receptors on various cells of immune system and its association with the gene polymorphism were investigated. Determining the levels of membrane-bound TNF α receptors on peripheral blood mononuclear cells (PBMCs) was performed by flow cytometry using BD QuantiBRITE calibration particles. Soluble TNF α receptor (sTNFRs) levels were determined by ELISA and genotyping was determined by PCR-RFLP. Homozygous TT individuals at SNP -609G/T TNFRI (rs4149570) showed lower levels of sTNFRI compared to GG genotype carriers. Homozygous carriers of CC genotype at SNP -1207G/C TNFRI (rs4149569) had lower expression densities of membrane-bound TNFRI on intact CD14(+) monocytes compared to individuals with the GC genotype. The frequency differences in the CD3(+) and CD19(+) cells expressing TNFRII in relation to SNP -1709A/T TNFRII (rs652625) in healthy individuals were also determined. The genotype CC in SNP -3609C/T TNFRII (rs590368) was associated with a lower percentage of CD14(+) cells expressing TNFRII compared to individuals with the CT genotype. Patients with rheumatoid arthritis had no significant changes in the frequencies of genotypes. Reduced frequency was identified for the combination TNFRI -609GT + TNFRII -3609CC only. The polymorphisms in genes represent one of cell type-specific mechanisms affecting the expression levels of membrane-bound TNF α receptors and TNF α -mediated signaling.
    Full-text · Article · Mar 2014 · Mediators of Inflammation
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    • "The CD83 and CD28 genes indicate a strong activation of the Th2 development and B lymphocytes [100-102]. The TNF receptor superfamily, receptor 1B and 6B (TnFRSF1B and TnFRSF6B) are a marker for T and B cell activation (TnFRSF1B) [103] and resistance to the pro-apoptotic activity of the FAS-ligand (TnFRSF6B) [104]. The TNFSF9 is a T-cell activation marker [105,106] and the CD40 is one of the key players in activation of both humoral and cell-mediated immune responses [107,108]. "
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    ABSTRACT: Immunotherapies, including vaccines, represent a potent tool to prevent or contain disease with high morbidity or mortality such as infections and cancer. However, despite their widespread use, we still have a limited understanding of the mechanisms underlying the induction of protective immune responses. Immunity is made of a multifaceted set of integrated responses involving a dynamic interaction of thousands of molecules; among those is a growing appreciation for the role the innate immunity (i.e. pathogen recognition receptors - PRRs) plays in determining the nature and duration (immune memory) of adaptive T and B cell immunity. The complex network of interactions between immune manipulation of the host (immunotherapy) on one side and innate and adaptive responses on the other might be fully understood only employing the global level of investigation provided by systems biology. In this framework, the advancement of high-throughput technologies, together with the extensive identification of new genes, proteins and other biomolecules in the "omics" era, facilitate large-scale biological measurements. Moreover, recent development of new computational tools enables the comprehensive and quantitative analysis of the interactions between all of the components of immunity over time. Here, we review recent progress in using systems biology to study and evaluate immunotherapy and vaccine strategies for infectious and neoplastic diseases. Multi-parametric data provide novel and often unsuspected mechanistic insights while enabling the identification of common immune signatures relevant to human investigation such as the prediction of immune responsiveness that could lead to the improvement of the design of future immunotherapy trials. Thus, the paradigm switch from "empirical" to "knowledge-based" conduct of medicine and immunotherapy in particular, leading to patient-tailored treatment.
    Full-text · Article · Sep 2011 · BMC Systems Biology
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    • "However, TNF-α does not work independently in the cell, but acts through binding to two receptors, TNF receptor superfamily, member 1A (TNFRSF1A or p55/p60) and TNF receptor superfamily, member 1B (TNFRSF1B, also called TNFR, p75/p80). TNFRSF1B is the larger of these receptors, being present on many cell types, and strongly expressed on stimulated T and B lymphocytes [14]. There is evidence that it regulates the binding of TNF-α to TNFRSF1A, and thus may regulate the levels of TNF-α necessary to stimulate the action of the transcription factor, nuclear factor-kappa B (NF-kB) [15]. "
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    ABSTRACT: Inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions with polygenic susceptibility. Interactions between TNF-alpha and TNF-alpha receptor play a fundamental role in inflammatory response. This study investigates the role that selected single nucleotide polymorphisms (SNPs) and haplotypes in the TNF-alpha receptor (TNSFRSF1B) gene play in the risk of IBD in a New Zealand Caucasian population. DNA samples from 388 CD, 405 UC, 27 indeterminate colitis patients, and 293 randomly selected controls, from Canterbury, New Zealand were screened for 3 common SNPs in TNSFRSF1B: rs1061622 (c.676T > C), rs1061624 (c.*1663A > G), and rs3397 (c.*1690T > C), using TaqMan technologies. Carrying the rs1061624 variant decreased the risk of UC in the left colon (OR 0.73, 95% CI = 0.54-1.00) and of being a smoker at diagnosis (OR 0.62; 95% CI = 0.40-0.96). Carrying the rs3397 variant decreased the risk of penetrating CD (OR 0.62, 95% CI = 0.40-0.95). Three marker haplotype analyses revealed highly significant differences between CD patients and control subjects (chi(2) = 29.9, df = 7, P = .0001) and UC cases and controls (chi(2) = 46.3, df = 7, P < .0001). We conclude that carrying a 3-marker haplotype in the TNSFRSF1B gene may increase (e.g., haplotype of GGC was 2.9-fold more in the CD or UCpatients) or decrease (e.g., TGT was 0.47-fold less in UC patients) the risk of IBD in a New Zealand Caucasian population.
    Full-text · Article · May 2009 · Gastroenterology Research and Practice
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