Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2

Laínez, Begoña; Fernández‐Real, José Manuel; Romero, Xavier; Esplugues, Enric; Cañete, Juan D.; Ricart, Wifredo; Engel, Pablo

doi:10.1093/intimm/dxh014

Cited by 59 publications

(68 citation statements)

References 44 publications

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“…Several genes have been shown to produce both [85] soluble and membrane-associated protein isoforms by selective incorporation of exons encoding transmembrane regions. In particular, several tumor necrosis factor receptor (TNFR) genes are alternatively spliced in a regulated manner to produce either soluble or membrane-associated signal-transducing forms [10][11][12][13][14][15]. Xing et al [16] showed that alternative inclusion/exclusion of membrane-spanning regions is a common outcome of alternative splicing, a result that was corroborated in a mouse-specific study [17].…”

Section: Introductionmentioning

confidence: 99%

The evolving roles of alternative splicing

Lareau

Green

Bhatnagar

et al. 2004

Current Opinion in Structural Biology

283

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Alternative splicing is now commonly thought to affect more than half of all human genes. Recent studies have investigated not only the scope but also the biological impact of alternative splicing on a large scale, revealing that its role in generating proteome diversity may be augmented by a role in regulation. For instance, protein function can be regulated by the removal of interaction or localization domains by alternative splicing. Alternative splicing can also regulate gene expression by splicing transcripts into unproductive mRNAs targeted for degradation. To fully understand the scope of alternative splicing, we must also determine how many of the predicted splice variants represent functional forms. Comparisons of alternative splicing between human and mouse genes show that predominant splice variants are usually conserved, but rare variants are less commonly shared. Evolutionary conservation of splicing patterns suggests functional importance and provides insight into the evolutionary history of alternative splicing. The definition of functional splicing has evolved to match our increased understanding of gene expression.At the same time that we realized the human genome has far fewer genes than expected, we began to appreciate the full extent of alternative splicing. Many concluded that alternative splicing led to proteome expansion, bridging a perceived complexity gap. However, complexity is not determined simply by proteome size; it also encompasses interactions and regulation. Recently, we have begun to better understand alternative splicing as a regulatory process, contributing to biological complexity through its ability to control the expression of proteins. A recent paper provides a modern definition of functional splicing: ''An mRNA variant can be defined as being 'functional' if it is required during the life-cycle of the organism and activated in a regulated manner'' [2 ]. In some cases, functional splice forms may not even be required in their own right, but their production is required to regulate active protein levels. Moreover, the meaning of 'required' can be generalized by defining functional splicing as that which conveys a selective advantage.Well before alternative splicing was known to be widespread, studies showed that control of splicing could act as a general on/off switch to regulate gene expression [3]. Work on mRNA stability in Caenorhabditis elegans indicated that alternative splicing of serine/argininerich (SR) proteins, themselves involved in alternative splicing, could regulate their expression [4]. Recently, the combination of large-scale studies, enabled by the large data sets now available (Table 1), and studies of individual alternatively spliced genes has shed light on the regulatory roles and evolution of alternative splicing.Large-scale studies of the regulatory impact of alternative splicingThe first large-scale studies of alternative splicing were inventory-style analyses, designed to determine the extent of alternative splicing. The results of those surveys, tha...

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Section: Introductionmentioning

confidence: 99%

The evolving roles of alternative splicing

Lareau

Green

Bhatnagar

et al. 2004

Current Opinion in Structural Biology

283

View full text Add to dashboard Cite

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“…In general, preanalytic conditions are critical in the assessment of sCD40L concentrations. Some reports document the effects of specimen type (serum and Potential role of selected biomarkers for predicting the presence and extent of coronary artery disease 2 Statistical significance of differences in continuous variables between groups of patients was analysed by means of Mann -Whitney U test; α=0.05 was adopted as a level of significance for all tests and statistically significant results are given in bold and denoted by * 2 Statistical significance of differences in continuous variables between groups of patients was analysed by means of Mann -Whitney U test; α=0.05 was adopted as a level of significance for all tests and statistically significant results are given in bold and denoted by * MMP-3, matrix-metalloproteinase-3; CAD, coronary artery disease 1 Statistical significance was analysed by means of ML Chi-square test; α=0.05 was adopted as a level of significance for all tests and statistically significant results are given in bold and denoted plasma), processing (time and temperature), and commercial reagent selection on sCD40L ELISA results 27,28 . High-sensitivity ELISA assay suitable for plasma and serum testing (Bender MedSystems) was used.…”

Section: Discussionmentioning

confidence: 99%

“…The results can in part be affected by specimen type: in our study blood serum was tested. As for Halldorsdottir et al the optimum strategy would be to measure sCD40L in platelet-free plasma 28 . Variability in statin administration could play its role as well (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Potential Role of Selected Biomarkers for Predicting the Presence and Extent of Coronary Artery Disease

Gřiva¹,

Náplava²,

Špendlíková³

et al. 2010

BIOMED PAP

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“…Other members of the TNF receptor family and several cytokine receptors that are found as soluble receptors are generated by alternative splicing (28)(29)(30)(31). We recently identified a biologically active soluble TNF-a receptor 2 isoform (DS-TNFR2) that was generated by alternative splicing and that antagonised TNF-a action in in vivo studies (32).…”

Section: Introductionmentioning

confidence: 99%

“…DS-TNFR2 was present in the serum of healthy individuals (32). We aimed to a) confirm the existence of DS-TNFR2 mRNA in peripheral monocytes from healthy subjects; and b) to evaluate circulating DS-TNFR2 in association with insulin action in vivo.…”

Section: Introductionmentioning

confidence: 99%

An alternative spliced variant of circulating soluble tumor necrosis factor-α receptor-2 is paradoxically associated with insulin action

Fernández-Real¹,

Strączkowski²,

Laínez³

et al. 2006

eur j endocrinol

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Objective: Serum concentrations of soluble tumor necrosis factor-a (TNF-a) receptor 2 (sTNFR2) are associated with insulin resistance. In a recent study, we provided evidence for the existence of a biologically active form of sTNFR2 produced by alternative splicing (DS-TNFR2). We aimed to evaluate whether this circulating DS-TNFR2 is associated with insulin action in humans. Design and methods: Real time PCR (light cycler technology) evaluated DS-TNFR2 expression in monocytes. DS-TNFR2 was measured using a monoclonal antibody against an epitope present in TNFR2 (first 14 residues of the juxtamembrane region) but predicted to be absent in soluble proteolytic cleavage-produced TNFR2. Insulin sensitivity was measured using euglycemic hyperinsulinemic clamp (n ¼ 76) and homeostatic model of assessment (HOMA) value in a replication study of 223 subjects. Results: Real time PCR confirmed gene expression of DS-TNFR2 in monocytes from healthy subjects. A significant and positive association was found between serum DS-TNFR2 concentration and insulin sensitivity (P ¼ 0.032, n ¼ 76). This association was most significant in subjects with normal glucose tolerance (r ¼ 0.44, P ¼ 0.002). The subjects in whom DS-TNFR2 was detectable were more insulin sensitive than those with undetectable DS-TNFR2 (42.12^22.08 vs 31.711 6.95 mmol £ kg 21 £ min 21, P ¼ 0.039). DS-TNFR2 was inversely associated with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, fasting serum glucose, serum triglycerides and serum uric acid concentration and with the HOMA value (P ¼ 0.03) in the replication study. Circulating DS-TNFR2 declined with increased number of components of the metabolic syndrome. Conclusion: Native sTNFR2 and DS-TNFR2 show opposite associations with insulin action. DS-TNFR2 might play a role as a counterpart of the proinflammatory environment associated with insulin resistance. 154 723-730 European Journal of Endocrinology

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Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2

Cited by 59 publications

References 44 publications

The evolving roles of alternative splicing

The evolving roles of alternative splicing

Potential Role of Selected Biomarkers for Predicting the Presence and Extent of Coronary Artery Disease

An alternative spliced variant of circulating soluble tumor necrosis factor-α receptor-2 is paradoxically associated with insulin action

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