Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The replication genes (rep) of the virulence plasmid pYVe439-80 of Yersinia enterocolitica were localized and characterized by restriction endonuclease analysis. Comparison with pIB1, a virulence plasmid of Y. pseudotuberculosis, indicates that while the plasmids carry homologous rep genes their location with respect to the highly conserved 'calcium region' is different. This replication function is thermosensitive. Mini-derivatives of pYVe439-80 appear to be rather unstable. The region of pYVe439-80 containing homology to the incD determinant of F was shown to contain a plasmid-stabilization system (par). The region encoding par was characterized by restriction endonuclease analysis. pIB1 contained an homologous par region but located differently. The pYV plasmids thus underwent rearrangements during their divergent evolution. While the positions of rep and par in the two plasmids are inverted with respect to the surrounding loci, our determination of the orientation of each locus rules out the hypothesis of a simple inversion of a quadrant of pYV. The gene encoding YOP5, a 26 kDa protein encoded by pIB1, was cloned on a mobilizable vector and introduced in Y. enterocolitica W22708 containing pYVe227 (indistinguishable from pYVe439-80), mutated in the homologous gene. The recombinant Y. enterocolitica secreted YOP5. Hence, the transcriptional activation and secretion systems of pYVe227 act on a yop gene from pIB1 and on its product, indicating that these systems are interchangeable.
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PMID:The replication, partition and yop regulation of the pYV plasmids are highly conserved in Yersinia enterocolitica and Y. pseudotuberculosis. 322 Nov 96

Interleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in host defense. It has been predicted that IL-6 may fold as a 4 alpha-helix bundle structure with up-up-down-down topology. Despite a high degree of sequence similarity (42%) the human and mouse IL-6 polypeptides display distinct species-specific activities. Although human IL-6 (hIL-6) is active in both human and mouse cell assays, mouse IL-6 (mIL-6) is not active on human cells. Previously, we demonstrated that the 5 C-terminal residues of mIL-6 are important for activity, conformation, and stability (Ward LD et al., 1993, Protein Sci 2:1472-1481). To further probe the structure-function relationship of this cytokine, we have constructed several human/mouse IL-6 hybrid molecules. Restriction endonuclease sites were introduced and used to ligate the human and mouse sequences at junction points situated at Leu-62 (Lys-65 in mIL-6) in the putative connecting loop AB between helices A and B, at Arg-113 (Val-117 in mIL-6) at the N-terminal end of helix C, at Lys-150 (Asp-152 in mIL-6) in the connecting loop CD between helices C and D, and at Leu-178 (Thr-180 in mIL-6) in helix D. Hybrid molecules consisting of various combinations of these fragments were constructed, expressed, and purified to homogeneity. The conformational integrity of the IL-6 hybrids was assessed by far-UV CD. Analysis of their biological activity in a human bioassay (using the HepG2 cell line), a mouse bioassay (using the 7TD1 cell line), and receptor binding properties indicates that at least 2 regions of hIL-6, residues 178-184 in helix D and residues 63-113 in the region incorporating part of the putative connecting loop AB through to the beginning of helix C, are critical for efficient binding to the human IL-6 receptor. For human IL-6, it would appear that interactions between residues Ala-180, Leu-181, and Met-184 and residues in the N-terminal region may be critical for maintaining the structure of the molecule; replacement of these residues with the corresponding 3 residues in mouse IL-6 correlated with a significant loss of alpha-helical content and a 200-fold reduction in activity in the mouse bioassay. A homology model of mIL-6 based on the X-ray structure of human granulocyte colony-stimulating factor is presented.
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PMID:Structure-function analysis of human IL-6: identification of two distinct regions that are important for receptor binding. 753 47

Receptors for interleukin-6 (IL-6) occur in body fluids in soluble form, as well. This is an approx. 50 kDa protein with the ability to bind IL-6. The soluble IL-6 receptor (sIL-6R)/IL-6 complex can attach to membrane anchored gp130, a molecule associated with the signal transduction induced by IL-6 and by other related cytokines. Earlier we described the appearance of sIL-6R in various body fluids of autoimmune patients. In this study using reverse transcriptase polymerase chain reaction (RT-PCR) we isolated and characterised a truncated form of amplified cDNA reverse-transcribed from IL-6 receptor mRNA both from human hepatoma cell line HepG2 and mononuclear cells from inflammatory bowel disease (IBD) patients. Using digestion by Pvu II restriction endonuclease and direct nucleotide sequencing we conclude that alternative splicing is likely involved in generation of sIL-6R. Our further experiments suggest that IL-6 and recombinant sIL-6R themselves do not influence the alternative splicing of IL-6 receptor gene.
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PMID:Generation of 'truncated' interleukin-6 receptor (IL-6R) mRNA by alternative splicing; a possible source of soluble IL-6R. 1039 66

Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of the insulin-producing islet beta cells. It is likely that several genetic and environmental factors contribute to this process. There is increasing evidence showing that polymorphisms in cytokine genes may play an important role in modifying the immune response. Interleukin-6 (IL-6) is a cytokine that has been implicated in a number of immune-mediated diseases. Further, there is a polymorphism at position -174 (G(-174)C) of the promoter region of the IL-6 gene that may alter the expression of the gene. In this study, the G(-174)C polymorphism was investigated in 257 Caucasoid patients with type 1 diabetes, 53 two-parent-proband trios, and 120 normal, healthy controls. DNA was amplified using amplimers that flank the G(-174)C site, and the products were digested with the restriction endonuclease NlaIII to detect the G or the C allele. The homozygous G,G(-174) genotype was increased in the patients compared with the normal controls (50.6% vs. 33.3%, p < 0.002), with a decrease in the C,C genotype in the patients compared with the controls (12.5% vs. 24.2%, respectively, p < 0.004). In the 53 trios studied, the G allele was transmitted in 29 of 53 informative meioses. There was no association with age at onset of diabetes or the presence of diabetic complications. In conclusion, these results suggest that the IL-6 gene may contribute to the genetic susceptibility to type 1 diabetes.
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PMID:A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus. 1105 76

Interleukin-6 (IL6) has come to be regarded as a potential osteoporotic factor because it has stimulatory effects on cells of the osteoclast lineage, and, thus, may play a role in the pathogenesis of bone loss associated with estrogen deficiency. We previously described association of the IL6 microsatellite with bone mineral density (BMD), as well as genetic linkage of the IL6 locus to human osteoporosis, by means of sib-pair analysis. However, the molecular mechanism by which this locus regulates BMD remains unknown. Accordingly, we searched for polymorphisms in the 5' and 3' flanking regions and in all five exons of the IL6 gene in a Japanese population sample. We identified three single-nucleotide sequence variations: a C/G substitution at nucleotide (nt) -634 in the promoter region, a G/A substitution at nt 4391 in the 3' noncoding region, and a variation in the AnTn tract around nt -447. The last of these had already been observed in Caucasians, as well as in Japanese. The single-nucleotide polymorphism at -634 created a restriction site for the BsrBI endonuclease, and the frequency of the minor (G) allele was 0.184. Five haplotypes were constructed among three variations examined in the population. Linkage disequilibrium was observed between the variation at -634 and the variation at 4391, as well as between the variation at -634 and the AnTn tract variation. We found a significant correlation, in 470 subjects, between the presence of the G allele and decreased BMD, by analysis of variance. When BMD values were compared among the three genotypic groups (G/G, G/C, C/C) at nt -634, BMD was lowest among the G/G homozygotes (mean +/- SD; 0.284 +/- 0.062g/cm2), highest among the C/C homozygotes (0.314 +/- 0.059g/cm2), and intermediate among the heterozygotes (0.303 +/- 0.066g/cm2; P < 0.05). Given the several lines of evidence from different genetic studies, we suggest that IL6 is, indeed, one of the genes affecting bone metabolism, in which variations can lead to osteoporosis.
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PMID:A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density. 1135 17

The transcription factor X-box binding protein 1 (XBP-1) is essential for the differentiation of plasma cells and the unfolded protein response (UPR). Here we show that UPR-induced splicing of XBP-1 by the transmembrane endonuclease IRE1 is required to restore production of immunoglobulin in XBP-1-/- mouse B cells, providing an integral link between XBP-1, the UPR and plasma cell differentiation. Signals involved in plasma cell differentiation, specifically interleukin-4, control the transcription of XBP-1, whereas its post-transcriptional processing is dependent on synthesis of immunoglobulins during B cell differentiation. We also show that XBP-1 is involved in controlling the production of interleukin-6, a cytokine that is essential for plasma cell survival. Thus, signals upstream and downstream of XBP-1 integrate plasma cell differentiation with the UPR.
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PMID:Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. 1266 Jul 29

It is well established that interleukin-6 (IL-6) is an essential growth factor for multiple myeloma (MM) and patients with increased IL-6 levels have a poor prognosis. In healthy subjects, the presence of the C allele at a polymorphic site (-174 G/C) of the IL-6 gene is related to low IL-6 levels. In view of the potential association of this particular polymorphism with IL-6 concentration, and the relevance of IL-6 in MM pathogenesis, the objective of the present study was to investigate the prevalence of IL-6 (-174 G/C) promoter polymorphism and its association with development of MM in Brazilian individuals. We investigated the prevalence of these alleles in 52 patients and 60 healthy subjects (matched by age, sex, and race) of a Brazilian population. Thirty patients were male (42.4%), 24 (46.2%) were white and the median age at diagnosis was 58.5 years (range: 28 to 84 years). To determine the IL-6 (-174 G/C) polymorphism, molecular analysis was performed by polymerase chain reaction followed by endonuclease restriction digestion. The genotype distributions observed in the group of patients were 4% CC, 42% GC and 54% GG. The C allele frequency was 0.25. These results were similar to the control group, suggesting no impact of this polymorphism on the susceptibility to MM.
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PMID:Analysis of polymorphism at site -174 G/C of interleukin-6 promoter region in multiple myeloma. 1727 64

Interleukin-6 (IL-6) is a multifunctional cytokine produced by different cell types, including monocytes, lymphocytes, endothelial and mesangial cells. Deregulated production of IL-6 was found to be involved in mesangial proliferative glomerulonephritis. We investigated whether the single nucleotide polymorphism (SNP) in the promoter region of the IL-6 gene is associated with a development of chronic glomerulonephritis (CGN). The study group consisted of 541 patients with CGN. Of those 338 already progressed to ESRD. The control group involved 253 healthy individuals. All subjects were genotyped for the -634 C/G polymorphism of the IL-6 gene by polymerase chain reaction (PCR). PCR product was digested with BsrBI restriction endonuclease and analyzed on 3% agarose. The allele and genotype frequencies were similar between CGN patients in a pre-dialysis stage and control subjects. Significantly increased frequency of the G allele was observed in the ESRD patients (13% vs. 6% in pre-dialysis stage, P < 0.01). After dividing ESRD patients according to time from reported disease onset to ESRD, those with time < or =5 years showed even higher G allele frequency (21% vs. 13% in entire ESRD group). Interestingly, most of the GG homozygotes were in this faster progressing group. Both subgroups were comparable for sex, age, BMI, total cholesterol and serum creatinine. The multivariate logistic regression analysis revealed that the IL-6 genotype with the G allele was an independent risk factor of progression to ESRD (P < 0.001). Our results indicate that the IL-6 -634 G/C polymorphism may be a possible risk factor for faster progression of chronic glomerulonephritis to ESRD. It is also possible that this polymorphism is in linkage disequilibrium with another functional polymorphism in the II-6 gene or its vicinity.
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PMID:Interleukin-6 gene polymorphism and faster progression to end-stage renal failure in chronic glomerulonephritis. 1765 29

This study examined a possible association of the G>C polymorphism at nucleotide -174 in the promoter region of the interleukin-6 (IL-6) gene (rs1800795) with the prevalence of diabetic complications in 235 patients with type 1 and 498 patients with type 2 diabetes. Genotyping was performed using polymerase chain reaction (PCR) and subsequent cleavage by Nla III restriction endonuclease. Analyzing all diabetic patients together demonstrated that 301 patients (41.1%) carried the GG genotype, 114 (15.6%) the CC genotype, and 318 (43.3%) were heterozygous for the GC genotype. However, there was no correlation of any of the genotypes with the prevalence of diabetic nephropathy or diabetic neuropathy, but subjects with the CC genotype had a significantly higher prevalence of diabetic retinopathy compared to patients with the GC and GG genotype (p=0.016). This association was mainly lost when a logistic regression model was adjusted for diabetes duration (p=0.07). Consistently, a weak but not significant association of the polymorphism with diabetic retinopathy was observed when type 1 and type 2 diabetic patients were analyzed separately (patients with type 1 diabetes: p=0.12; patients with type 2 diabetes: p=0.09). Analogically, no association of the polymorphism was found for diabetic nephropathy or diabetic neuropathy in these groups. In conclusion these data suggest no major influence of the -174G>C variant in the promoter region of the IL-6 gene on the development of microvascular complications in patients with diabetes.
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PMID:The -174G>C IL-6 gene promoter polymorphism and diabetic microvascular complications. 1914 96

The active control of mRNA degradation has emerged as a key regulatory mechanism required for proper gene expression in the immune system. An adenosine/uridine (AU)-rich element (ARE) is at the heart of a first regulatory system that promotes the rapid degradation of a multitude of cytokine and chemokine mRNAs. AREs serve as binding sites for a number of regulatory proteins that either destabilize or stabilize the mRNA. Several kinase pathways regulate the activity of ARE-binding proteins and thereby coordinate the expression of their target mRNAs. Small regulatory micro (mi)-RNAs represent a second system that enhances the degradation of several mRNAs encoding important components of signal transduction cascades that are activated during adaptive and innate immune responses. Specific miRNAs are important for the differentiation of T helper cells, class switch recombination in B cells, and the maturation of dendritic cells. Excitement in this area of research is fueled by the discovery of novel RNA elements and regulatory proteins that exert control over specific mRNAs, as exemplified by an endonuclease that was found to directly cleave interleukin-6 mRNA. Together, these systems make up an extensive regulatory network that controls decay rates of individual mRNAs in a precise manner and thereby orchestrates the dynamic expression of many factors essential for adaptive and innate immune responses. In this review, we provide an overview of relevant factors regulated at the level of mRNA stability, summarize RNA-binding proteins and miRNAs that control their degradation rates, and discuss signaling pathways operating within this regulatory network.
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PMID:Networks controlling mRNA decay in the immune system. 2195 41


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