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Title:
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Differential transcriptional and post-translational transcription factor 7-like regulation among nondiabetic individuals and type 2 diabetic patients.
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Author:
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Pradas-Juni, Marta; Nicod, Nathalie; Fernández-Rebollo, Eduardo; Gomis, Ramon, 1946-
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Notes:
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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. |
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Subject(s):
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-Diabetis
-Expressió gènica
-Biosíntesi
-Proteïnes
-Factors de transcripció
-Genètica molecular
-Diabetes
-Gene expression
-Biosynthesis
-Proteins
-Transcription factors
-Molecular genetics |
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Rights:
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(c) Endocrine Society, 2014
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Document type:
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Article
Article - Published version |
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Published by:
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Endocrine Society
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