c-Jun Amino-Terminal Kinase-1 Mediates Glucose-Responsive Upregulation of the RNA Editing Enzyme ADAR2 in Pancreatic Beta-Cells 英文参考文献.docVIP

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c-Jun Amino-Terminal Kinase-1 Mediates Glucose-Responsive Upregulation of the RNA Editing Enzyme ADAR2 in Pancreatic Beta-Cells 英文参考文献.doc

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c-Jun Amino-Terminal Kinase-1 Mediates Glucose-Responsive Upregulation of the RNA Editing Enzyme ADAR2 in Pancreatic Beta-Cells 英文参考文献

c-JunAmino-TerminalKinase-1MediatesGlucose- ResponsiveUpregulationoftheRNAEditingEnzyme ADAR2inPancreaticBeta-Cells LiuYang1.,PingHuang1.,FengLi1,LiyunZhao1,YongliangZhang1,ShoufengLi1,ZhenjiGan1¤, AnningLin2,WenjunLi1,YongLiu1* 1KeyLaboratoryofNutritionandMetabolism,InstituteforNutritionalSciences,ShanghaiInstitutesforBiologicalSciences,ChineseAcademyofSciences,Shanghai,China, 2StateKeyLaboratory ofCellBiology,Institute ofBiochemistryandCellBiology, ShanghaiInstitutesfor Biological Sciences, ChineseAcademy ofSciences, Shanghai, China Abstract A-to-IRNAeditingcatalyzedbythetwomainmembersoftheadenosinedeaminaseactingonRNA(ADAR)family,ADAR1 andADAR2,representsaRNA-basedrecodingmechanismimplicatedinavarietyofcellularprocesses.Previouslywehave demonstrated that the expression of ADAR2 in pancreatic islet b-cells is responsive to the metabolic cues and ADAR2 deficiencyaffectsregulatedcellularexocytosis.ToinvestigatethemolecularmechanismbywhichADAR2ismetabolically regulated, we found that in cultured b-cells and primary islets, the stress-activated protein kinase JNK1 mediates the upregulation of ADAR2 in response to changes of the nutritional state. In parallel with glucose induction of ADAR2 expression,JNKphosphorylationwasconcurrentlyincreasedininsulin-secretingINS-1b-cells.Pharmacologicalinhibitionof JNKs or siRNA knockdown of the expression of JNK1 prominently suppressed glucose-augmented ADAR2 expression, resulting in decreased efficiency of ADAR2 auto-editing. Consistently, the mRNA expression of Adar2 was selectively reducedintheisletsfromJNK1nullmiceincomparisonwiththatofwild-typelittermatesorJNK2nullmice,andablationof JNK1diminishedhigh-fatdiet-inducedAdar2expressionintheisletsfromJNK1nullmice.Furthermore,promoteranalysisof themouseAdar2geneidentifiedaglucose-responsiveregionandrevealedthetranscriptionfactorc-JunasadriverofAdar2 transcription. Taken together, these results demonstrate that JNK1 serves as a crucial component in mediating glucose- responsiv