Sp1 Is Essential for p16INK4a Expression in Human Diploid Fibroblasts during Senescence 英文参考文献.docVIP

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Sp1 Is Essential for p16INK4a Expression in Human Diploid Fibroblasts during Senescence 英文参考文献.doc

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Sp1 Is Essential for p16INK4a Expression in Human Diploid Fibroblasts during Senescence 英文参考文献

Sp1IsEssentialforp16INK4a ExpressioninHumanDiploid FibroblastsduringSenescence JunfengWu.,LixiangXue.,MoWeng,YingSun,ZongyuZhang,WengongWang*,TanjunTong* PekingUniversityResearchCenteronAging,DepartmentofBiochemistryandMolecularBiology,PekingUniversity,HealthScienceCenter,Beijing, China Background.p16INK4atumorsuppressorproteinhasbeenwidelyproposedtomediateentranceofthecellsintothesenescent stage.Promoterofp16INK4a genecontainsatleastfiveputativeGCboxes,namedGC-ItoV,respectively.Ourpreviousdata showed that a potential Sp1 binding site, within the promoter region from 2466 to 2451, acts as a positive transcription regulatory element. These results led us to examine how Sp1 and/or Sp3 act on these GC boxes during aging in cultured humandiploidfibroblasts.Methodology/PrincipalFindings.MutagenesisstudiesrevealedthatGC-I,IIandIV,especiallyGC- II,areessentialforp16INK4a geneexpressioninsenescentcells.Electrophoreticmobilityshiftassays(EMSA)andChIPassays demonstratedthatbothSp1andSp3bindtotheseelementsandthebindingactivityisenhancedinsenescentcells.Ectopic overexpressionofSp1,butnotSp3,inducedthetranscriptionofp16INK4a.BothSp1RNAiandMithramycin,aDNAintercalating agentthatinterfereswithSp1andSp3bindingactivities,reducedp16INK4ageneexpression.Inaddition,theenhancedbinding of Sp1 to p16INK4a promoter during cellular senescence appeared to be the result of increased Sp1 binding affinity, not an alterationinSp1proteinlevel.Conclusions/Significance.AlltheseresultssuggestthatGC-IIisthekeysiteforSp1binding andincreaseofSp1bindingactivityratherthanproteinlevelscontributestotheinductionofp16INK4a expressionduringcell aging. Citation: Wu J, Xue L, Weng M, Sun Y, Zhang Z, et al (2007) Sp1 Is Essential for p16INK4a Expression in Human Diploid Fibroblasts during Senescence.PLoSONE2(1):e164.doi:10.1371/journal.pone.0000164 INTRODUCTION was cultured in DMEM medium, containing 10% fetal bovine serum,100U/mlpenicillinand1mg/mlstreptomycin[28,29]. Normalhumancellsundergoafiniten