Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells 英文参考文献.docVIP

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Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells 英文参考文献.doc

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Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells 英文参考文献

ExpressionofTIP-1ConfersRadioresistanceofMalignant GliomaCells MiaojunHan1,3,4,HailunWang1,Hua-TangZhang3,ZhaozhongHan1,2,5* 1DepartmentofRadiationOncology,VanderbiltUniversity,Nashville,Tennessee,UnitedStatesofAmerica,2CancerBiology,VanderbiltUniversity,Nashville,Tennessee, UnitedStatesofAmerica,3KeyLaboratoryofAnimalModelsandHumanDiseaseMechanismsoftheChineseAcademyofSciencesYunnanProvince,KunmingInstitute ofZoology,Kunming,YunnanProvince,China,4GraduateSchool,ChineseAcademyofSciences,Beijing,China,5Vanderbilt-IngramCancerCenter,SchoolofMedicine, VanderbiltUniversity,Nashville,Tennessee,UnitedStatesofAmerica Abstract Background: Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combinedwithchemotherapeuticagentsbecauseoftheintrinsicoracquiredresistance.Inthisstudy,TIP-1wasidentified asonenovelproteinthatconfersresistanceofgliomacellstoIR. Methodology/Principal Findings: Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosisofhumanmalignantgliomasafterradiotherapy.Studieswithestablishedhumangliomacelllinesdemonstrated thatTIP-1depletionwithspecificshRNAssensitizedthecellstoIR,whereasanectopicexpressionofTIP-1protectedthe gliomacellsfromtheIR-inducedDNAdamageandcelldeath.BiochemicalstudiesindicatedthatTIP-1proteinpromoted p53ubiquitinationandresultedinareducedp53proteinlevel.Furthermore,p53anditsubiquitinationarerequiredforthe TIP-1regulatedcellularresponsetoIR.Ayeasttwo-hybridscreeningidentifiedthatTIP-1,throughitssinglePDZdomain, bindstothecarboxylterminusofLZAPthathasbeenstudiedasonetumorsuppressorfunctioningthroughARFbinding andp53activation.ItwasrevealedthatthepresenceofTIP-1enhancestheproteinassociationbetweenLZAPandARFand modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depletingTIP-1wi