Journal
CELL DEATH AND DIFFERENTIATION
Volume 16, Issue 11, Pages 1539-1550Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.99
Keywords
diabetes; pancreatic beta cells; DP5; ER stress; apoptosis
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Funding
- Communaute Francaise de Belgique - Actions de Recherche Concertees (ARC)
- Fonds National de la Recherche Scientifique (FNRS) Belgium
- Belgium State [IUAP P6/40]
- European Union [036903]
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Chronic inflammation and pro-inflammatory cytokines are important mediators of pancreatic beta-cell destruction in type 1 diabetes (T1D). We presently show that the cytokines IL-1 beta + IFN-gamma and different ER stressors activate the Bcl-2 homology 3 (BH3)-only member death protein 5 (DP5)/harakiri (Hrk) resulting in beta-cell apoptosis. Chemical ER stress-induced DP5 upregulation is JNK/c-Jun-dependent. DP5 activation by cytokines also involves JNK/c-Jun phosphorylation and is antagonized by JunB. Interestingly, cytokine-inducted DP5 expression precedes ER stress: mitochondrial release of cytochrome c and ER stress are actually a consequence of enhanced DP5 activation by cytokine-mediated nitric oxide formation. Our findings show that DP5 is central for beta-cell apoptosis after different stimuli, and that it can act up- and downstream of ER stress. These observations contribute to solve two important questions, namely the mechanism by which IL-1 beta + IFN-gamma induce beta-cell death and the nature of the downstream signals by which ER stress 'convinces' beta-cells to trigger apoptosis. Cell Death and Differentiation (2009) 16, 1539-1550; doi:10.1038/cdd.2009.99; published online 24 July 2009
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