Nuclear Receptor SHP Activates miR-206 Expression via a Cascade Dual Inhibitory Mechanism 英文参考文献.docVIP

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Nuclear Receptor SHP Activates miR-206 Expression via a Cascade Dual Inhibitory Mechanism 英文参考文献.doc

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Nuclear Receptor SHP Activates miR-206 Expression via a Cascade Dual Inhibitory Mechanism 英文参考文献

NuclearReceptorSHPActivatesmiR-206Expressionviaa CascadeDualInhibitoryMechanism GuishengSong,LiWang* DepartmentsofMedicineandOncologicalSciences,HuntsmanCancerInstitute,UniversityofUtahSchoolofMedicine,SaltLakeCity,Utah,UnitedStatesofAmerica Abstract MicroRNAsplayacriticalroleinmanyessentialcellularfunctionsinthemammalianspecies.However,limitedinformationis availableregardingtheregulationofmiRNAsgenetranscription.Microarrayprofilingandreal-timePCRanalysisrevealeda markeddown-regulationofmiR-206innuclearreceptorSHP2/2mice.TounderstandtheregulatoryfunctionofSHPwith regardtomiR-206geneexpression,wedeterminedtheputativetranscriptionalinitiationsiteofmiR-206andalsoitsfull lengthprimarytranscriptusingadatabaseminingapproachandRACE.WeidentifiedthetranscriptionfactorAP1binding sitesonthemiR-206promoterandfurthershowedthatAP1(c-Junandc-Fos)inducedmiR-206promotertransactivityand expressionwhichwasrepressedbyYY1.ChIPanalysisconfirmedthephysicalassociationofAP1(c-Jun)andYY1withthe endogenous miR-206 promoter. In addition, we also identified nuclear receptor ERRc (NR3B3) binding site on the YY1 promoterandshowedthatYY1promoterwastransactivatedbyERRc,whichwasinhibitedbySHP(NROB2).ChIPanalysis confirmedtheERRcbindingtotheYY1promoter.ForcedexpressionofSHPandAP1 inducedmiR-206expressionwhile overexpression of ERRc and YY1 reduced its expression. The effects of AP1, ERRc, and YY1 on miR-206 expression were reversedbysiRNAknockdownofeachgene,respectively.Thus,weproposeanovelcascade‘‘dualinhibitory’’mechanism governing miR-206 gene transcription by SHP: SHP inhibition of ERRc led to decreased YY1 expression and the de- repression of YY1 on AP1 activity, ultimately leading to the activation of miR-206. This is the first report to elucidate a cascaderegulatorymechanismgoverningmiRNAsgenetranscription. Citation: Song G, Wang L (2009) Nuclear Receptor SHP Activates miR-206 Expression via a Cascade Dual Inhibitory Mechanism. PLoS ONE 4(9): e6880. doi:10.1371/journal.pone.0006880 Ed