Novel Insights into the Global Proteome Responses of Insulin-Producing INS-1E Cells To Different Degrees of Endoplasmic Reticulum Stress
Exposure of insulin-secreting β-cells to inflammatory cytokines or high concentrations of free fatty acids, factors involved in the pathogenesis of type 1 and type 2 diabetes, leads to endoplasmic reticulum (ER) stress, β-cell dysfunction, and eventually apoptotic β-cell death. The aim of this study...
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Veröffentlicht in: | Journal of proteome research 2010-10, Vol.9 (10), p.5142-5152 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Exposure of insulin-secreting β-cells to inflammatory cytokines or high concentrations of free fatty acids, factors involved in the pathogenesis of type 1 and type 2 diabetes, leads to endoplasmic reticulum (ER) stress, β-cell dysfunction, and eventually apoptotic β-cell death. The aim of this study was to investigate the impact of ER stress on β-cells at the protein level to evaluate the contribution of post-transcriptional and post-translational changes in ER stress-induced β-cell damage. INS-1E cells were exposed in vitro to the ER-stress inducer cyclopiazonic acid (CPA) at two concentrations, and protein changes were evaluated using 2D-DIGE. CPA, 25 μM, led to massive apoptosis, accompanied by a near complete protein translation shut-down. CPA, 6.25 μM, led to adaptation of the β-cells to ER stress. Identification of the differentially expressed proteins in the two conditions led to the discovery of a clear pattern of defense pathways, with post-translational modifications playing a crucial role. Key alterations included inhibition of insulin translation and post-translational modifications in ER chaperones HYOU1 and HSPA5. Also, a central role for 14−3−3 proteins is suggested. In conclusion, INS-1E cells are highly sensitive to ER stress, leading to important post-transcriptional and post-translational modifications that may contribute to β-cell dysfunction and death. |
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ISSN: | 1535-3893 1535-3907 |
DOI: | 10.1021/pr1004086 |