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A Polymorphism in the 3' Untranslated Region of the Gene for Tumor Necrosis Factor Receptor 2 Modulates Reporter Gene Expression

Department de Fisiologia (I.P., B.L., M.Bu., E.E.), Facultat de Biologia, Universitat de Barcelona, E-08028 Barcelona, Spain; Diabetes, Endocrinology, and Nutrition Research Unit (B.L., J.M.F.-R.), University of Girona, Hospital of Girona "Dr Josep Trueta," E-17007 Girona, Spain; and Universitat Rovira-Virgili (M.Br., J.V.), 43003 Tarragona, Spain

Address all correspondence and requests for reprints to: Dr. Enric Espel, Department Fisiologia, Facultat Biologia, Diagonal 645, 08028 Barcelona, Spain. E-mail: eespel{at}ub.edu.

The gene encoding the human TNF receptor (TNFR) 2 contains polymorphisms in the 3' untranslated region (UTR). Previous studies have shown that some variant alleles in this region are associated with obesity and insulin resistance. However, the effect of these polymorphisms on the expression of TNFR2 has not been studied to date. To examine the role played by different haplotypes in the control of TNFR2 expression (haplotypes A1-A5, referring to nucleotides 1663 G/A, 1668 T/G, and 1690 T/C), we introduced these sequences into the 3'-UTR of a heterologous reporter gene and expressed the corresponding constructs in a human T-cell line. We demonstrate that a 485-nt fragment of the TNFR2 3'-UTR that contains a U-rich region decreases reporter expression and that haplotypes A1-A4 exert a stronger effect than A5. Furthermore, time-course assays of mRNA stability using actinomycin D revealed that haplotypes A1-A4 destabilize the mRNA. The proximal TNFR2 3'-UTR, independently of haplotype differences, responded to T-cell activation by increasing mRNA decay. Electromobility shift analysis demonstrated that protein(s) found in T-cell extracts bind to the 485-nt fragment. We suggest that an increased rate of TNFR2 mRNA decay protects cells from unrestrained TNF effects and that this protection is weakened in A5 subjects. These findings may explain the association of this haplotype with obesity and increased leptin levels.

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