NKX2-5 Regulates the Expression of β-Catenin and GATA4 in Ventricular Myocytes 英文参考文献.docVIP

NKX2-5RegulatestheExpressionofb-Cateninand GATA4inVentricularMyocytes AliM.Riazi1*,JunK.Takeuchi1,5,LisaK.Hornberger2,SyedHassanZaidi3,FaribaAmini1,JohnColes1, BenoitG.Bruneau1,4,GlenS.VanArsdell1 1LabattFamilyHeartCentre,HospitalforSickChildren,Toronto,Ontario,Canada,2FetalCardiovascularProgram,PediatricHeartCenterandFetalTreatmentCenter, School of Medicine, University of California San Francisco, San Francisco, California, United States of America, 3Division of Cardiology, University Health Network, University of Toronto, Toronto, Ontario, Canada, 4Gladstone Institute of Cardiovascular Disease, Department of Pediatrics, University of California San Francisco, San Francisco,California,UnitedStatesofAmerica,5DivisionofCardiovascularResearch,Global-EdgeInstitute,TokyoInstituteofTechnology,Yokohama,Japan Abstract Background: The molecular pathway that controls cardiogenesis is temporally and spatially regulated by master transcriptionalregulatorssuchasNKX2-5,Isl1,MEF2C,GATA4,andb-catenin.Theinterplaybetweenthesefactorsandtheir downstream targets are not completely understood. Here, we studied regulation of b-catenin and GATA4 by NKX2-5 in humanfetalcardiacmyocytes. Methodology/PrincipalFindings:UsingantisenseinhibitionwedisruptedtheexpressionofNKX2-5andstudiedchangesin expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased b-catenin while GATA4 was decreased.WedemonstratedthatthisregulationwasconferredbybindingofNKX2-5tospecificelements(NKEs)inthe promoter region oftheb-catenin andGATA4genes. Usingpromoter-luciferase reporter assay combined withmutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of b- catenin,andupregulationofGATA4byNKX2-5. Conclusions:ThisstudysuggeststhatNKX2-5modulatestheb-cateninandGATA4transcriptionalactivitiesindeveloping humancardiacmyocytes. Citation: Riazi AM, Takeuchi JK, Hornberger LK, Zaidi SH, Amini F, et al. (2009) NKX2-5 Regulates