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Cell Signal. 2014 Sep;26(9):1792-9. doi: 10.1016/j.cellsig.2014.04.006. Epub 2014 Apr 12.

Inhibition of human insulin gene transcription and MafA transcriptional activity by the dual leucine zipper kinase.

Author information

1
Department of Pharmacology, University Medical Center Göttingen, Göttingen, Germany.
2
Institute of Clinical Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
3
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
4
Institut Curie, CNRS UMR 3347, INSERM U1021, Paris Sud University Centre de Recherche, Orsay, France.
5
Department of Pharmacology, University Medical Center Göttingen, Göttingen, Germany; Institute of Clinical Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DZHK (German Centre for Cardiovascular Research) partner site Hamburg/Kiel/Lübeck, Hamburg, Germany; Institute of Pharmacy, University of Hamburg, Hamburg, Germany. Electronic address: e.oetjen@uke.uni-hamburg.de.

Abstract

Insulin biosynthesis is an essential β-cell function and inappropriate insulin secretion and biosynthesis contribute to the pathogenesis of diabetes mellitus type 2. Previous studies showed that the dual leucine zipper kinase (DLK) induces β-cell apoptosis. Since β-cell dysfunction precedes β-cell loss, in the present study the effect of DLK on insulin gene transcription was investigated in the HIT-T15 β-cell line. Downregulation of endogenous DLK increased whereas overexpression of DLK decreased human insulin gene transcription. 5'- and 3'-deletion human insulin promoter analyses resulted in the identification of a DLK responsive element that mapped to the DNA binding-site for the β-cell specific transcription factor MafA. Overexpression of DLK wild-type but not its kinase-dead mutant inhibited MafA transcriptional activity conferred by its transactivation domain. Furthermore, in the non-β-cell line JEG DLK inhibited MafA overexpression-induced human insulin promoter activity. Overexpression of MafA and DLK or its kinase-dead mutant into JEG cells revealed that DLK but not its mutant reduced MafA protein content. Inhibition of the down-stream DLK kinase c-Jun N-terminal kinase (JNK) by SP600125 attenuated DLK-induced MafA loss. Furthermore, mutation of the serine 65 to alanine, shown to confer MafA protein stability, increased MafA-dependent insulin gene transcription and prevented DLK-induced MafA loss in JEG cells. These data suggest that DLK by activating JNK triggers the phosphorylation and degradation of MafA thereby attenuating insulin gene transcription. Given the importance of MafA for β-cell function, the inhibition of DLK might preserve β-cell function and ultimately retard the development of diabetes mellitus type 2.

KEYWORDS:

DLK; Diabetes mellitus; Insulin gene transcription; MafA

PMID:
24726898
PMCID:
PMC5006626
DOI:
10.1016/j.cellsig.2014.04.006
[Indexed for MEDLINE]
Free PMC Article

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