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Survival of pancreatic beta cells is partly controlled by a TCF7L2-p53-p53INP1-dependent pathway.

Zhou, Yuedan LU ; Zhang, Enming LU ; Berggreen, Christine LU ; Jing, Xingjun; Osmark, Peter LU ; Lang, Stefan LU ; Cilio, Corrado LU ; Göransson, Olga LU ; Groop, Leif LU and Renström, Erik LU , et al. (2012) In Human Molecular Genetics 21. p.196-207
Abstract
The transcription factor T-cell factor 7-like 2 (TCF7L2) confers type 2 diabetes risk mainly through impaired insulin secretion, perturbed incretin effect and reduced beta-cell survival. The aim of this study was to identify the molecular mechanism through which TCF7L2 influences beta-cell survival. TCF7L2 target genes in INS-1 cells were identified using Chromatin Immunoprecipitation. Validation of targets was obtained by: siRNA silencing, real-time quantitative polymerase chain reaction, electrophoretic mobility shift assay, luciferase reporter assays and western blot. Apoptosis rate was measured by DNA degradation and caspase-3 content. Islet viability was estimated by measuring metabolic rate. TCF7L2 binds to 3646 gene promoters in... (More)
The transcription factor T-cell factor 7-like 2 (TCF7L2) confers type 2 diabetes risk mainly through impaired insulin secretion, perturbed incretin effect and reduced beta-cell survival. The aim of this study was to identify the molecular mechanism through which TCF7L2 influences beta-cell survival. TCF7L2 target genes in INS-1 cells were identified using Chromatin Immunoprecipitation. Validation of targets was obtained by: siRNA silencing, real-time quantitative polymerase chain reaction, electrophoretic mobility shift assay, luciferase reporter assays and western blot. Apoptosis rate was measured by DNA degradation and caspase-3 content. Islet viability was estimated by measuring metabolic rate. TCF7L2 binds to 3646 gene promoters in INS-1 cells in high or low glucose, including Tp53, Pten, Uggt1, Adamts9 and Fto. SiRNA-mediated reduction in TCF7L2 activity resulted in increased apoptosis and increased expression of Tp53, which resulted in elevated p53 protein activity and an increased expression of the p53 target gene Tp53inp1 (encoding p53-induced-nuclear-protein 1). Reversing the increase in p53INP1 protein expression, seen after Tcf7l2 silencing, protected INS-1 cells from Tcf7l2 depletion-induced apoptosis. This result was replicated in primary rat islets. The risk T-allele of rs7903146 is associated with increased TCF7L2 mRNA expression and transcriptional activity. On the other hand, in vitro silencing of TCF7L2 lead to increased apoptosis. One possibility is that the risk T-allele increases expression of an inhibitory TCF7L2 isoform with lower transcriptional activity. These results identify the p53-p53INP1 pathway as a molecular mechanism through which TCF7L2 may affect beta-cell survival and established a molecular link between Tcf7l2 and two type 2 diabetes-associated genes, Tp53inp1 and Adamts9. (Less)
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published
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Human Molecular Genetics
volume
21
pages
196 - 207
publisher
Oxford University Press
external identifiers
  • wos:000297865100018
  • pmid:21965303
  • scopus:83455206083
ISSN
0964-6906
DOI
10.1093/hmg/ddr454
language
English
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yes
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f752d4cf-3460-446a-a1c6-b3e05c42e7b2 (old id 2200873)
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http://www.ncbi.nlm.nih.gov/pubmed/21965303?dopt=Abstract
date added to LUP
2011-11-02 07:42:13
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2017-09-03 04:51:26
@article{f752d4cf-3460-446a-a1c6-b3e05c42e7b2,
  abstract     = {The transcription factor T-cell factor 7-like 2 (TCF7L2) confers type 2 diabetes risk mainly through impaired insulin secretion, perturbed incretin effect and reduced beta-cell survival. The aim of this study was to identify the molecular mechanism through which TCF7L2 influences beta-cell survival. TCF7L2 target genes in INS-1 cells were identified using Chromatin Immunoprecipitation. Validation of targets was obtained by: siRNA silencing, real-time quantitative polymerase chain reaction, electrophoretic mobility shift assay, luciferase reporter assays and western blot. Apoptosis rate was measured by DNA degradation and caspase-3 content. Islet viability was estimated by measuring metabolic rate. TCF7L2 binds to 3646 gene promoters in INS-1 cells in high or low glucose, including Tp53, Pten, Uggt1, Adamts9 and Fto. SiRNA-mediated reduction in TCF7L2 activity resulted in increased apoptosis and increased expression of Tp53, which resulted in elevated p53 protein activity and an increased expression of the p53 target gene Tp53inp1 (encoding p53-induced-nuclear-protein 1). Reversing the increase in p53INP1 protein expression, seen after Tcf7l2 silencing, protected INS-1 cells from Tcf7l2 depletion-induced apoptosis. This result was replicated in primary rat islets. The risk T-allele of rs7903146 is associated with increased TCF7L2 mRNA expression and transcriptional activity. On the other hand, in vitro silencing of TCF7L2 lead to increased apoptosis. One possibility is that the risk T-allele increases expression of an inhibitory TCF7L2 isoform with lower transcriptional activity. These results identify the p53-p53INP1 pathway as a molecular mechanism through which TCF7L2 may affect beta-cell survival and established a molecular link between Tcf7l2 and two type 2 diabetes-associated genes, Tp53inp1 and Adamts9.},
  author       = {Zhou, Yuedan and Zhang, Enming and Berggreen, Christine and Jing, Xingjun and Osmark, Peter and Lang, Stefan and Cilio, Corrado and Göransson, Olga and Groop, Leif and Renström, Erik and Hansson, Ola},
  issn         = {0964-6906},
  language     = {eng},
  pages        = {196--207},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Survival of pancreatic beta cells is partly controlled by a TCF7L2-p53-p53INP1-dependent pathway.},
  url          = {http://dx.doi.org/10.1093/hmg/ddr454},
  volume       = {21},
  year         = {2012},
}