Cloning and Expression of Human Lymphotoxin mRNA Derived from a Human T Cell Hybridoma1

Kobayashi, Yoshiro; Miyamoto, Daisei; Asada, Makoto; Obinata, Masuo; Osawa, Toshiaki

doi:10.1093/oxfordjournals.jbchem.a121765

Cited by 21 publications

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“…As TNFA and TNFB genes are tandemly arranged within the HLA complex, and it has been shown that the TNFB gene polymorphisms influence the level of production of the TNFA protein [19], [52]. Studies indicate that variations at both TNFA -308 G/A and TNFB +252 A/G can affect TNFA production levels [21], [53].…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor B (TNFB) Genetic Variants and Its Increased Expression Are Associated with Vitiligo Susceptibility

et al. 2013

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Genetic polymorphisms in TNFB are involved in the regulation of its expression and are found to be associated with various autoimmune diseases. The aim of the present study was to determine whether TNFB +252A/G (rs909253) and exon 3 C/A (rs1041981) polymorphisms are associated with vitiligo susceptibility, and expression of TNFB and ICAM1 affects the disease onset and progression. We have earlier reported the role of TNFA in autoimmune pathogenesis of vitiligo, and we now show the involvement of TNFB in vitiligo pathogenesis. The two polymorphisms investigated in the TNFB were in strong linkage disequilibrium and significantly associated with vitiligo. TNFB and ICAM1 transcripts were significantly increased in patients compared to controls. Active vitiligo patients showed significant increase in TNFB transcripts compared to stable vitiligo. The genotype-phenotype analysis revealed that TNFB expression levels were higher in patients with GG and AA genotypes as compared to controls. Patients with the early age of onset and female patients showed higher TNFB and ICAM1 expression. Overall, our findings suggest that the increased TNFB transcript levels in vitiligo patients could result, at least in part, from variations at the genetic level which in turn leads to increased ICAM1 expression. For the first time, we show that TNFB +252A/G and exon 3 C/A polymorphisms are associated with vitiligo susceptibility and influence the TNFB and ICAM1 expression. Moreover, the study also emphasizes influence of TNFB and ICAM1 on the disease progression, onset and gender bias for developing vitiligo.

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Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor B (TNFB) Genetic Variants and Its Increased Expression Are Associated with Vitiligo Susceptibility

et al. 2013

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“…2), as a previously reported polymorphism in the 3' untranslated region was described with a frequency of 6% (25) . No homozygous 2.5-kb EcoRI sub- Figure (10,34,36) or contain in exchange ACC = Thr at amino acid position 26 (9, 35,36). We wondered whether the NcoI RFLP is linked with the presence of AAC at amino acid position 26.…”

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confidence: 99%

Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production.

Messer

Spengler

Jung

et al. 1991

The Journal of Experimental Medicine

526

360

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SummarySince a dysregulated synthesis of tumor necrosis factor a (TNF-a) may be involved in the pathogenesis of autoimmune diseases, it was ofinterest to precisely locate the recently reported Ncol restriction fragment length polymorphism (RFLP) of the TNF-a region . However, by mapping of 56.8 kb of overlapping cosmid clones and direct sequencing, we could localize the polymorphic Ncol restriction site within the first intron of the TNF-0 gene and not in the TNF-a gene. To study whether regulatory mechanisms are affected by this polymorphism, we analyzed the TNF-a/TNF-0 production of phytohemagglutinin-stimuated peripheral blood mononuclear cells ofindividuals homozygous for the TNF-0 Ncol RFLP by ELISA and concomitant Northern blot analysis. On days 2-4 after stimulation with mitogen, the TNFB*1 allele corresponding to a 5.3-kb Ncol fragment presented with a significantly higher TNF-0 response. A mRNA analysis demonstrated that higher protein levels of TNF-0 correlate also with increased amounts ofTNF-0 transcripts . No allelic association was found in respect to TNF-a production . To further investigate a possible allelic influence on transcription, we determined the DNA sequence of 2 kb ofthe 5' portion of our cloned TNFB*2 allele and compared it with the available TNF-0 sequences. By computer-aided recognition motif search ofDNA binding factors, we report putative binding sites conserved between mouse and man in the 5' flanking region as well as in intron 1 ofthe TNF-0 gene, found also in other cytokine promoter sequences. In addition, by polymerase chain reaction amplification and sequencing of 740 by of the 5' part of TNF-0 of individuals typed homozygously for the Ncol RFLP, we could show that amino acid position 26 is conserved as asparagine in the TNFB*1 and as threonine in the TNFB* 2 sequence. A previously reported, EcoRI RFLP in the 3' untranslated region of TNF-0 does not segregate with either of the two alleles. Thus, four TNFB alleles can de defined at the DNA level .

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“…Second, although a TATA box is located 20 nucleotides upstream of the defined transcription start site (TSS) of LTA exon 1, the starting nucleotide of LTA mRNAs is rather variable. LTA mRNAs have been described that initiate in the proximal promoter region (−915 to −1; Figure 1) at positions −379 (GenBank accession number DQ123821.1 from primary human PBMCs) (22) and −185 (NM_001159740.1), in exon 1 at positions +33 (D12614.1 from a B cell line and NM_000595.2), +35 (DQ123822.1 from primary human PBMCs) (22), +102 (X01393) and +115 (D00102.1 from a T cell line) (24), and in exon 2 at position +454 (BC034729.1 from a lymphoma) (25). Collectively, these data suggest that the nature of LTA transcripts likely is influenced by cell type and by the stimulating agent and that the LTA gene may be transcribed from several alternate core promoters.…”

Section: Introductionmentioning

confidence: 99%

A Stimulation-Dependent Alternate Core Promoter Links Lymphotoxin α Expression with TGF-β1 and Fibroblast Growth Factor-7 Signaling in Primary Human T Cells

Yokley

Selby

2013

The Journal of Immunology

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Lymphotoxin alpha (LT-α) regulates many biologic activities, yet little is known of the regulation of its gene. In this study, the contribution to LTA transcriptional regulation of the region between the transcription and translation start sites (downstream segment) was investigated. The LTA downstream segment was found to be required for and alone to be sufficient for maximal transcriptional activity in both T and B lymphocytes. The latter observation suggested that an alternate core promoter might be present in the downstream segment. Characterization of LTA mRNAs isolated from primary and from transformed human T cells under different stimulation conditions identified eight unique transcript variants (TVs) including one (LTA TV8) that initiated within a polypyrimidine tract near the 3′ end of the downstream segment. Further investigation determined that the LTA downstream segment alternate core promoter that produces the LTA TV8 transcript most likely consists of a Sp1 binding site and an initiator element and that factors involved in transcription initiation (Sp1, TFII-I and RNA polymerase II) bind to this LTA region in vivo. Interestingly, the LTA downstream segment alternate core promoter was active only after specific cellular stimulation and was the major promoter utilized when human T cells were stimulated with transforming growth factor (TGF)-β1 and fibroblast growth factor (FGF)-7. Most importantly, this study provides evidence of a direct link for crosstalk between T cells and epithelial/stromal cells that has implications for lymphotoxin signaling by T cells in the cooperative regulation of various processes typically associated with TGF-βR and FGF-R2 signaling.

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Cloning and Expression of Human Lymphotoxin mRNA Derived from a Human T Cell Hybridoma1

Cited by 21 publications

References 0 publications

Tumor Necrosis Factor B (TNFB) Genetic Variants and Its Increased Expression Are Associated with Vitiligo Susceptibility

Tumor Necrosis Factor B (TNFB) Genetic Variants and Its Increased Expression Are Associated with Vitiligo Susceptibility

Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production.

A Stimulation-Dependent Alternate Core Promoter Links Lymphotoxin α Expression with TGF-β1 and Fibroblast Growth Factor-7 Signaling in Primary Human T Cells

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