Dynamic Telomerase Gene Suppression via Network Effects of GSK3 Inhibition 英文参考文献.docVIP

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Dynamic Telomerase Gene Suppression via Network Effects of GSK3 Inhibition 英文参考文献.doc

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Dynamic Telomerase Gene Suppression via Network Effects of GSK3 Inhibition 英文参考文献

DynamicTelomeraseGeneSuppressionviaNetwork EffectsofGSK3Inhibition AlanE.Bilsland1,StaceyHoare1,KatrinaStevenson1,JanePlumb1,NatividadGomez-Roman1 ,Claire Cairney1,SharonBurns1,KyleLafferty-Whyte1,JonRoffey2,TimHammonds2,W.NicolKeith1* 1Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Bearsden, Glasgow, United Kingdom,2CancerResearchTechnologyLtd.,WolfsonInstituteforBiomedicalResearch,TheCruciformBuilding,London,UnitedKingdom Abstract Background:Telomerasecontrolstelomerehomeostasisandcellimmortalityandisapromisinganti-cancertarget,butfew small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti- telomerasetherapeuticsandmayrevealnewtargetstoinhibithTERTexpression. Methodology/PrincipalFindings:Inafocusedpromoterscreen,severalGSK3inhibitorssuppressedhTERTreporteractivity. GSK3inhibitionusing6-bromoindirubin-39-oximesuppressedhTERTexpression,telomeraseactivityandtelomerelengthin several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodellinginvolvingSp1,STAT3,c-Myc,NFkB,andp53occurredattheendogenoushTERTpromoter.RNAiscreeningof the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors.ProlongedinhibitortreatmentscauseddynamicexpressionbothofhTERTandofc-Jun,p53,STAT3,ARandc-Myc. Conclusions/Significance: Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomerelengthhomeostasis.GSK3inhibitionisaclinicalstrategyforseveralchronicdiseases.Theseresultsimplythatit may also be useful in cancer therapy. However, the complex network eff