Dysbindin-1, a Schizophrenia-Related Protein, Functionally Interacts with the DNA- Dependent Protein Kinase Complex in an Isoform-Dependent Manner 英文参考文献.docVIP

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Dysbindin-1, a Schizophrenia-Related Protein, Functionally Interacts with the DNA- Dependent Protein Kinase Complex in an Isoform-Dependent Manner 英文参考文献.doc

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Dysbindin-1, a Schizophrenia-Related Protein, Functionally Interacts with the DNA- Dependent Protein Kinase Complex in an Isoform-Dependent Manner 英文参考文献

Dysbindin-1,aSchizophrenia-RelatedProtein, FunctionallyInteractswiththeDNA-DependentProtein KinaseComplexinanIsoform-DependentManner SatokoOyama1,HidekuniYamakawa1,NoboruSasagawa1,YoshioHosoi2,EugeneFutai1,ShoichiIshiura1* 1DepartmentofLifeSciences,GraduateSchoolofArtsandSciences,UniversityofTokyo,Meguro-ku,Tokyo,Japan,2DepartmentofRadiologicalTechnology,Schoolof HealthSciences,NiigataUniversity,Niigata-shi,Niigata,Japan Abstract DTNBP1hasbeenrecognizedasaschizophreniasusceptiblegene,anditsproteinproduct,dysbindin-1,isdown-regulated inthebrainsofschizophrenicpatients.However,littleisknownaboutthephysiologicalroleofdysbindin-1inthecentral nervous system. We hypothesized that disruption of dysbindin-1 with unidentified proteins could contribute to pathogenesis and the symptoms of schizophrenia. GST pull-down from human neuroblastoma lysates showed an associationofdysbindin-1withtheDNA-dependentproteinkinase(DNA-PK)complex.TheDNA-PKcomplexinteractsonly withspliceisoformsAandB,butnotwithC.WefoundthatisoformsAandBlocalizedinnucleus,wherethekinasecomplex exist,whereastheisoformCwasfoundexclusivelyincytosol.Furthermore,resultsofphosphorylationassaysuggestthat the DNA-PK complex phosphorylated dysbindin-1 isoforms A and B in cells. These observations suggest that DNA-PK regulatesthedysbindin-1isoformsAandBbyphosphorylationinnucleus.IsoformCdoesnotcontainexonsfrom1to6. Sinceschizophrenia-relatedsinglenucleotidepolymorphisms(SNPs)occurintheseintronsbetweenexon1andexon6,we suggestthattheseSNPsmightaffectsplicingofDTNBP1,whichleadstoimpairmentofthefunctionalinteractionbetween dysbindin-1andDNA-PKinschizophrenicpatients. Citation:OyamaS,YamakawaH,SasagawaN,HosoiY,FutaiE,etal.(2009)Dysbindin-1,aSchizophrenia-RelatedProtein,FunctionallyInteractswiththeDNA- DependentProteinKinaseComplexinanIsoform-DependentManner.PLoSONE4(1):e4199.doi:10.1371/journal.pone.0004199 Editor:BaiLu,NationalInstitutesofHealth,UnitedStatesofAmerica ReceivedSeptember17,2008;AcceptedDecember3,2008;Publish