Basal Cancer Cell Survival Involves JNK2 Suppression of a Novel JNK1c-JunBcl-3 Apoptotic Network 英文参考文献.docVIP

BasalCancerCellSurvivalInvolvesJNK2Suppressionofa NovelJNK1/c-Jun/Bcl-3ApoptoticNetwork ShafiqUddinAhmed,JoMilner* YCRP53ResearchUnit,DepartmentofBiology,UniversityofYork,York,UnitedKingdom Abstract Background:Theregulationofapoptosisunderbasal(non-stress)conditionsiscrucialfornormalmammaliandevelopment and also for normal cellular turnover in different tissues throughout life. Deficient regulation of basal apoptosis, or its perturbation, can result in impaired development and/or disease states including cancer. In contrast to stress-induced apoptosistheregulationofapoptosisunderbasalconditionsispoorlyunderstood.Toaddressthisissuewehavecompared basal-andstress-inducedapoptosisinhumanepithelialcellsofnormalandcancerousorigins.Forthispurposewefocussed ourstudyontheopposingpro-apoptoticJNK/anti-apoptoticNFk Bpathways. Methodology/Principal Findings: Combinatorial RNAi plus gene knockout were employed to access and map basal regulatorypathwaysofapoptosis.Follow-on,in-depthanalysesincludedexogenousexpressionofphosphorylationmutants andchromatinimmunoprecipitation.WedemonstratethatbasalapoptosisisconstitutivelysuppressedbyJNK2inarange of human cancer cell lines. This effect was not observed in non-cancer cells. Silencing JNK2 by RNAi resulted in JNK1- dependentapoptosisofcancercellsviaup-regulationoftheAP-1factorc-Jun.UnexpectedlywediscoveredthatJNK1and c-Jun promote basal apoptosis in the absence of ‘‘activating phosphorylations’’ typically induced by stress. Hypo- phosphorylated c-Jun accumulated to high levels following JNK2 silencing, auto-regulated its own expression and suppressed expression of Bcl-3, an unusual IkB protein and regulator of NFkB. Basal apoptosis was mediated by componentsoftheTNFaresponsepathwaybutwasmechanisticallydistinctfromTNFa-inducedapoptosis. Conclusions/Significance:Ourresultsdemonstratethatmechanisticallydistinctpathwaysoperatetoregulateapoptosisin mammaliancellsunderbasal(physiological)versusstress-inducedconditions.Wealsodescribeanovela