Nestin Modulates Glucocorticoid Receptor Function by Cytoplasmic Anchoring 英文参考文献.docVIP

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Nestin Modulates Glucocorticoid Receptor Function by Cytoplasmic Anchoring 英文参考文献.doc

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Nestin Modulates Glucocorticoid Receptor Function by Cytoplasmic Anchoring 英文参考文献

NestinModulatesGlucocorticoidReceptorFunctionby CytoplasmicAnchoring RudolphReimer1.,HeikeHelmbold1.,BeataSzalay1,ChristianHagel2,HeinrichHohenberg1 ,Wolfgang Deppert1,WolfgangBohn1* 1Heinrich-Pette-Institute for Experimental Virology and Immunology at the University of Hamburg, Hamburg, Germany, 2Institute of Neuropathology, Universita¨tsklinikum Hamburg-Eppendorf,Hamburg,Germany Abstract Nestinisthecharacteristicintermediatefilament(IF)proteinofrapidlyproliferatingprogenitorcellsandregeneratingtissue. NestincopolymerizeswithclassIIIIF-proteins,mostlyvimentin,intoheteromericfilaments.Itsexpressionisdownregulated with differentiation. Here we show that a strong nestin expression in mouse embryo tissue coincides with a strong accumulationoftheglucocorticoidreceptor(GR),akeyregulatorofgrowthanddifferentiationinembryonicdevelopment. MicroscopicstudiesonculturedcellsshowanassociationofGRwithIFscomposedofvimentinandnestin.Cellslacking nestin,butexpressingvimentin,orcellsexpressingvimentin,butlackingnestinaccumulateGRinthenucleus.Completing thesenetworkswithanexogenousnestin,respectivelyanexogenousvimentinrestorescytoplasmicanchoringofGRtothe IFsystem.Thus,heteromericfilamentsprovidethebasisforanchoringofGR.Thereactionpatternwithphospho-GRspecific antibodiesandthepresenceofthechaperoneHSC70suggestthatspecificallytheunligandedreceptorisanchoredtotheIF system. Ligand addition releases GR from IFs and shifts the receptor into the nucleus. Suppression of nestin by specific shRNAabolishesanchoringofGR,inducesitsaccumulationinthenucleusandprovokesanirreversibleG1/Scellcyclearrest. SuppressionofGRpriortothatofnestinpreventsentryintothearrest.Thedatagiveevidencethatnestin/vimentinspecific anchoring modulates growth suppression by GR. We hypothesize that expression of nestin is a major determinant in suppressionofanti-proliferativeactivityofGRinundifferentiatedtissueandfacilitatesactivationofthisgrowthcontrolina precisetissueanddifferentiationdependentmanner. Citation: Reime