| Autor: |
Pradas-Juni M; Diabetes and Obesity Research Laboratory (M.P.-J., N.N., E.F-R., R.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (M.P.-J., N.N., E.F.-R., R.G.), 08017 Barcelona, Spain; Department of Medicine (R.G.), University of Barcelona, 08036 Barcelona, Spain; and Hospital Clínic de Barcelona (R.G.), 08036 Barcelona, Spain., Nicod N, Fernández-Rebollo E, Gomis R |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular endocrinology (Baltimore, Md.) [Mol Endocrinol] 2014 Sep; Vol. 28 (9), pp. 1558-70. Date of Electronic Publication: 2014 Jul 24. |
| DOI: |
10.1210/me.2014-1065 |
| Abstrakt: |
Human genetic studies have revealed that the T minor allele of single nucleotide polymorphism rs7903146 in the transcription factor 7-like 2 (TCF7L2) gene is strongly associated with an increased risk of diabetes by 30%-40%. Molecular and clinical studies are of great importance for understanding how this unique variation in TCF7L2 influences type 2 diabetes (T2D) onset and progression. At the molecular level, some studies have been performed in diabetic mice and pancreatic islets from healthy human donors. Whereas TCF7L2 mRNA levels are up-regulated in islets, protein levels are down-regulated. We performed studies on TCF7L2 splicing, mRNA expression, and protein levels in immortalized human lymphocytes from nondiabetic individuals and T2D patients carrying the C/C or the at-risk T/T genotype. Our results show differential expression of TCF7L2 splice variants between nondiabetic and T2D patients carrying the at-risk genotype, as well as differences in protein levels. Therefore, we investigated the regulation of splice variants, and our results propose that splicing of exon 4 is under control of the serine-arginine-rich factor transformer 2 β (TRA2B). Finally, we studied the endoplasmic reticulum stress pathways, looking for a posttranslational explanation. We saw a shift in the activation of these pathways between nondiabetic individuals and T2D patients carrying the at-risk genotype. These results suggest that, in human immortalized lymphocytes carrying the at-risk T/T genotype, first the differential expression of TCF7L2 splice variants implies a regulation, at least for exon 4, by TRA2B and second, the differential protein levels between both T/T carriers point to a different activation of endoplasmic reticulum stress pathways. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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