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Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs
| Journal | Diabetologia |
| Publisher | Springer Berlin / Heidelberg |
| ISSN | 0012-186X (Print) 1432-0428 (Online) |
| Issue | Volume 50, Number 5 / May, 2007 |
| Category | Article |
| DOI | 10.1007/s00125-007-0609-0 |
| Pages | 1006-1014 |
| Subject Collection | Medicine |
| SpringerLink Date | Friday, March 02, 2007 |
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Article
Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation
of insulin mRNAs
P. Pirot1, N. Naamane1, F. Libert2, N. E. Magnusson3, T. F. Ørntoft3, A. K. Cardozo1 and D. L. Eizirik1 
| (1) |
Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Route de Lennik, 808-CP-618, 1070 Brussels, Belgium |
| (2) |
Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium |
| (3) |
Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark |
Received: 14 November 2006 Accepted: 2 January 2007 Published online: 1 March 2007
Abstract
Aims/hypothesis Pancreatic beta cells respond to endoplasmic reticulum (ER) stress by activating the unfolded protein response. If the stress
is prolonged, or the adaptive response fails, apoptosis is triggered. We used a ‘homemade’ microarray specifically designed
for the study of beta cell apoptosis (the APOCHIP) to uncover mechanisms regulating beta cell responses to ER stress.
Materials and methods A time course viability and microarray analysis was performed in insulin-producing INS-1E cells exposed to the reversible
ER stress inducer cyclopiazonic acid (CPA). Modification of selected genes was confirmed by real-time RT-PCR, and the observed
inhibition of expression of the insulin-1 ( Ins1) and insulin-2 ( Ins2) genes was further characterised in primary beta cells exposed to a diverse range of agents that induce ER stress.
Results CPA-induced ER stress modified the expression of 183 genes at one or more of the time points studied. The expression of most
of these genes returned to control levels after a 3 h recovery period following CPA removal, with all cells surviving. Two
groups of genes were particularly affected by CPA, namely, those related to cellular responses to ER stress, which were mostly
upregulated, and those related to differentiated beta cell functions, which were downregulated. Levels of Ins1 and Ins2 mRNAs were severely decreased in response to CPA treatment as a result of degradation, and there was a concomitant increase
in the level of IRE1 activation.
Conclusions/interpretation In this study we provide the first global analysis of beta cell molecular responses to a severe ER stress, and identify the
early degradation of mRNA transcripts of the insulin genes as an important component of this response.
Electronic supplementary material The online version of the article (doi:10.1001/s00125-007-0609-0) contains supplementary material, which is available to authorised users.
Keywords Apoptosis - CPA - Cyclopiazonic acid - Diabetes mellitus - Endoplasmic reticulum stress - Insulin - Interleukin-1 - Pancreatic beta cells
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Supplemental Material
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