An Intron-Retaining Splice Variant of Human Cyclin A2, Expressed in Adult Differentiated Tissues, Induces a G1S Cell Cycle Arrest In Vitro 英文参考文献.docVIP

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An Intron-Retaining Splice Variant of Human Cyclin A2, Expressed in Adult Differentiated Tissues, Induces a G1S Cell Cycle Arrest In Vitro 英文参考文献.doc

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An Intron-Retaining Splice Variant of Human Cyclin A2, Expressed in Adult Differentiated Tissues, Induces a G1S Cell Cycle Arrest In Vitro 英文参考文献

AnIntron-RetainingSpliceVariantofHumanCyclinA2, ExpressedinAdultDifferentiatedTissues,InducesaG1/S CellCycleArrestInVitro ArataHonda1,2,3.,YannickValogne2,3.¤,MyriamBouNader2,3,ChristianBre′chot2,3,JamilaFaivre2,3 * 1TokyoMetropolitanHealthandMedicalTreatmentCorporation,EbaraHospital,Tokyo,Japan,2INSERM,U785,CentreHe′patobiliaire,Villejuif,France,3Universite′Paris- Sud,Faculte′ deMe′decine, Villejuif,France Abstract Background:HumancyclinA2isakeyregulatorofSphaseprogressionandentryintomitosis.Alternativesplicevariantsof theG1andmitoticcyclinshavebeenshowntointerferewithfull-lengthcyclinfunctionstomodulatecellcycleprogression andarethereforelikelytoplayaroleindifferentiationoroncogenesis.ThealternativesplicingofhumancyclinA2hasnot yetbeenstudied. Methodology/Principal Findings: Sequence-specific primers were designed to amplify various exon–intron regions of cyclin A2 mRNA in cell lines and human tissues. Intron retaining PCR products were cloned and sequenced and then overexpressedinHeLacells.Thesubcellularlocalizationofthesplicevariantswasstudiedusingconfocalandtime-lapse microscopy,andtheirimpactonthecellcyclebyflowcytometry,immunoblottingandhistoneH1kinaseactivity.Wefound asplicevariantofcyclinA2mRNAcalledA2V6thatpartlyretainsIntron6.ThegeneexpressionpatternofA2V6mRNAin humantissueswasnoticeablydifferentfromthatofwild-typecyclinA2(A2WT)mRNA.Itwaslowerinproliferatingfetal tissues and stronger in some differentiated adult tissues, especially, heart. In transfected HeLa cells, A2V6 localized exclusivelyinthecytoplasmwhereasA2WTaccumulatedinthenucleus.WeshowthatA2V6inducedaclearG1/Scellcycle arrestassociatedwithap21andp27upregulationandaninhibitionofretinoblastomaproteinphosphorylation.LikeA2WT, A2V6boundCDK2,buttheA2V6/CDK2complexdidnotphosphorylatehistoneH1. Conclusion/Significance:Thisstudyhasrevealedthatsomehighlydifferentiatedhumantissuesexpressanintron-retaining cyclinA2mRNAthatinducedaG1/Sblockinvitro.Contrarytofull-lengthcyclinA2,whichregulatescellprolifera