Journal
CELLULAR SIGNALLING
Volume 28, Issue 4, Pages 272-283Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2016.01.002
Keywords
Dual leucine zipper kinase; Nuclear localization signal; CREB; beta-cell apoptosis; Diabetes
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Funding
- Deutsche Forschungsgemeinschaft [OE 181/3-1, KE 660/5-2]
- JDRF
- ERC
- Fritz-Thyssen Stiftung
- Niemann Stiftung
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The dual leucine zipper kinase DLK induces beta-cell apoptosis by inhibiting the transcriptional activity conferred by the beta-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to beta-cell loss and ultimately diabetes. Within its kinase domain DLK shares high homology with the mixed lineage kinase (MLK) 3, which is activated by tumor necrosis factor (TNF) alpha and interleukin (IL)-1 beta, known prediabetic signals. In the present study, the regulation of DLK in beta-cells by these cytokines was investigated. Both, TNF alpha and IL-1 beta induced the nuclear translocation of DLK. Mutations within a putative nuclear localization signal (NLS) prevented basal and cytokine-induced nuclear localization of DLK and binding to the importin receptor importin alpha, thereby demonstrating a functional NLS within DLK. DLK NLS mutants were catalytically active as they phosphorylated their down-stream kinase c-Jun N-terminal kinase to the same extent as DLK wild-type but did neither inhibit CREB-dependent gene transcription nor transcription conferred by the promoter of the anti-apoptotic protein BCL-xL In addition, the beta-cell apoptosis-inducing effect of DLK was severely diminished by mutation of its NLS. In a murine model of prediabetes, enhanced nuclear DLK was found. These data demonstrate that DLK exerts distinct functions, depending on its subcellular localization and thus provide a novel level of regulating DLK action. Furthermore, the prevention of the nuclear localization of DLK as induced by prediabetic signals with consecutive suppression of beta-cell apoptosis might constitute a novel target in the therapy of diabetes mellitus. (C) 2016 Elsevier Inc. All rights reserved.
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