Cell-specific inositol 1,4,5 trisphosphate 3-kinase mediates epithelial cell apoptosis in response to oxidative stress in Drosophila

Terhzaz, S., Finlayson, A. J., Stirrat, L., Yang, J., Tricoire, H., Woods, D. J., Dow, J. A.T. and Davies, S. A. (2010) Cell-specific inositol 1,4,5 trisphosphate 3-kinase mediates epithelial cell apoptosis in response to oxidative stress in Drosophila. Cellular Signalling, 22(5), pp. 737-748. (doi:10.1016/j.cellsig.2009.12.009)

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Abstract

Organismal stress responses to oxidative stress are relevant to ageing and disease and involve key cell-/tissue -specific signal transduction mechanisms. Using Drosophila, an established in vivo model for stress studies, we show that cell-specific inositol phosphate signaling specifically via Inositol 1,4,5 trisphosphate 3-kinase (InsP3 3-K, IP3K), negatively regulates organismal responses to oxidative stress. We demonstrate that the Drosophila Malpighian tubule (equivalent to vertebrate kidney and liver) is a key epithelial sensor for organismal oxidative stress responses: precise targeting of either gain-of-function constructs of Drosophila IP3Ks (IP3K-1 and IP3K-2), or loss-of-function (RNAi) constructs to only one cell type in tubule reversibly modulates survival of stress-challenged adult flies. In vivo, targeted IP3K-1 directly increases H2O2 production, pro-apoptotic caspase-9 activity and mitochondrial membrane potential. The mitochondrial calcium load in tubule principal cells - assessed by luminescent and fluorescent genetically-encoded mitochondrial calcium reporters - is significantly increased by IP3K-1 under oxidative stress conditions, leading to apoptosis. The Drosophila orthologues of human apoptotic bcl-2 genes include debcl and buffy. Oxidative stress challenge does not modulate gene expression of either debcl or buffy in tubules; and altered debcl expression does not influence survival rates under oxidative stress challenge. Finally, targeted over-expression of either debcl or buffy to tubule principal cells does not impact on tubule caspase-9 activity. Thus, IP3K-1 modulates epithelial cell apoptosis without involvement of bcl-2-type proteins.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dow, Professor Julian and Terhzaz, Dr Selim and Davies, Professor Shireen and Stirrat, Mrs Laura and Yang, Dr Jingli
Authors: Terhzaz, S., Finlayson, A. J., Stirrat, L., Yang, J., Tricoire, H., Woods, D. J., Dow, J. A.T., and Davies, S. A.
Subjects:Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Cellular Signalling
Publisher:Elsevier
ISSN:0898-6568
ISSN (Online):1873-3913
Published Online:11 January 2010

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
415661Spatiotemporal filtering in calcium control of mitochondrial functionJulian DowBiotechnology and Biological Sciences Research Council (BBSRC)BB/D013852/1Institute of Molecular Cell and Systems Biology