Necdin, a Negative Growth Regulator, Is a Novel STAT3 Target Gene Down-Regulated in Human Cancer 英文参考文献.docVIP

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Necdin, a Negative Growth Regulator, Is a Novel STAT3 Target Gene Down-Regulated in Human Cancer 英文参考文献.doc

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Necdin, a Negative Growth Regulator, Is a Novel STAT3 Target Gene Down-Regulated in Human Cancer 英文参考文献

Necdin,aNegativeGrowthRegulator,IsaNovelSTAT3 TargetGeneDown-RegulatedinHumanCancer RachelHaviland1,StevenEschrich2,GregoryBloom2,YihongMa1,SusanMinton3,RichardJove4* ,W. DouglasCress1* 1Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America, 2Biomedical Informatics, Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America, 3Breast Cancer Program, Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America,4BeckmanResearchInstitute,CityofHopeNationalMedicalCenter,Duarte,California,UnitedStatesofAmerica Abstract Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primarytumors,andareknownforthetranscriptionalroletheyplayincontrollingcellgrowthandcellcycleprogression. However,theextentofSTAT3’sreachontranscriptionalcontrolofthegenomeasawholeremainsanimportantquestion. WepredictedthatthispersistentSTAT3signalingaffectsawidevarietyofcellularfunctions,manyofwhichstillremaintobe characterized.WetookabroadapproachtoidentifynovelSTAT3regulatedgenesbyexaminingchangesinthegenome- wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator,asanovelSTAT3targetgene,whoseexpressionisdown-regulatedatthemRNAandproteinlevelswhenSTAT3is constitutivelyactive.ThisrepressionisSTAT3dependent,sinceinhibitionofSTAT3usingsiRNArestoresNecdinexpression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanomaandadrug-resistantovariancancercellline.Furt