کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10814766 | 1058397 | 2016 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Distinct functions of the dual leucine zipper kinase depending on its subcellular localization
ترجمه فارسی عنوان
توابع متمایز کیناز زیپ لوکین دوگانه بسته به موقعیت محلی سلولیت آن
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
چکیده انگلیسی
The dual leucine zipper kinase DLK induces β-cell apoptosis by inhibiting the transcriptional activity conferred by the β-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to β-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) α and interleukin (IL)-1β, known prediabetic signals. In the present study, the regulation of DLK in β-cells by these cytokines was investigated. Both, TNFα and IL-1β 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 α, 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 β-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 β-cell apoptosis might constitute a novel target in the therapy of diabetes mellitus.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 28, Issue 4, April 2016, Pages 272-283
Journal: Cellular Signalling - Volume 28, Issue 4, April 2016, Pages 272-283
نویسندگان
Manuel Wallbach, Jorge Duque Escobar, Rohollah Babaeikelishomi, Marie-Jeannette Stahnke, Roland Blume, Sabine Schröder, Jenny Kruegel, Kathrin Maedler, Oliver Kluth, Ralph H. Kehlenbach, Nicolai Miosge, Elke Oetjen,