简介：Apoptosisisprimarilyexecutedbyactivecaspases,whicharederivedfromtheinactiveprocaspasezymogensthroughproteolyticcleavage.Wedeterminedthecrystalstructuresofacaspasezymogen,procaspase-7,andanactivecaspase-7withoutanyboundinhibitors.Comparedtotheinhibitor-boundcaspase-7,procaspase-7zymogenexhibitssignificantstructuraldifferencessurroundingthecatalyticcleft,whichprecludestheformationofaproductiveconformation.Proteolyticcleavageinbetweenthelargeandsmallsubunitsallowsrearrangementofessentialloopsintheactivesite,primingactivecaspase-7forinhibitor/substratebinding.Strikingly,bindingbyinhibitorscausesa180-degree-flippingoftheN-terminusinthesmallsubunit,whichinteractswithandstabilizesthecatalyticcleft.Theseanalysesrevealthestructuralmechanismsofcaspaseactivationanddemonstratethattheinhibitor/substratebindingisaprocessof

简介：Uponencounteringtheantigen(Ag),theimmunesystemcaneitherdevelopaspecificimmuneresponseofenteraspecificstateofunresponsiveness,tolerance.TheresponseofBcellstotheirspecificAgcanbeactivationandproliferation,leadingtotheimmuneresponse,oranergyandactivation-inducedcelldeath(AICD),leadingtotolerance.AICDinBlymphocytesisahighlyregulatedeventinitiatedbycrosslinkingoftheBcellreceptor(BCR).BCRengagementinitiatesseveralsignalingeventssuchasactivationofPLCγ,Ras,andPI3K,whichgenerallyspeaking,leadtosurvival.However,intheabsenceofsurvivalsignals(CD40orIL-4Rengagement),BCRcrosslinkingcanalsopromoteapoptoticsignaltransductionpathwayssuchasactivationofeffectorcaspases,expressionofpro-apoptoticgenes,andinhibitionofpro-survivalgenes.ThecomplexinterplaybetweensurvivalanddeathsignalsdeterminestheBcellfateand,consequently,theimmuneresponse.

简介：GelatinaseA(MMP-2)isconsideredtoplayacriticalroleincellmigrationandinvasion.Theproteinaseiscercetedfromthecellasaninactivezymogen.InvivoitispostulatedthatactivationofprogelationaseA(proMMP-2)takesplaceonthecellsurfacemediatedbymembrane-typematrixmetalloproteinases(MT-MMPs).RecentstudieshavedemonstratedthatproMMP-2isrecruitedtothecellsurfacebyinteractingwithtissueinhibitorofmetalloproteinases-2(TIMP-2)boundtoMT1-MMPbyformingaternarycomplex.FreeMT1-MMPcloselylocatedtotheternarycomplexthenactivatesproMMP-2onthecellsurface.MT1-MMPisfoundinculturedinvasivecancercellsattheinvadopodia.TheMT-MMP/TIMP-2/MMP-2systemthusprovideslocalizedexpressionofproteolysisoftheextracellularmatrixrequiredforcellmigration.

简介：

简介：TherearetwopossibleoutcomeswhenDNAdamageoccursinnormalmammaliancells:eitherinductionofcell-cyclecheckpointwhichinhibitstheprogressofthecellcyclesaswellasactivatesDNArepairpathways,oractivationofapoptosistoeliminatedamagedcells.Thep53tumour-suppressorgeneplaysakeyroleinselectingthesepathways.Inourpresentworks,thehumangastriccancercelllineAGSwastreatedwithtripchlorolide,apotentantitumorcompoundpurifiedfromaChineseherbTripterygiumWilfordiiHook.Singlecellgelelectrophoresis(Cometassay)showedthatthetreatmentoftripchlorolideresultedinDNAdamageinAGScells.ThedamagedAGScellswentthroughapoptosis,whichwastime-anddose-dependent.

简介：CellsregulatephospholipaseD(PLD)activityinresponsetonumerousextracellularsignals.Here,weinvestigatedtheinvolvementofPLDactivityintransforminggrowthfactor-β(TGF-β1)-mediatedgrowthinhibitionofepithelialcells.TGF-β1)-mediatedgrowthinhibitionofepithelialcells.TGF-β1inhibitsthegrowthofMDCK,Mv1Lu,andA-549cells.Inthepresenceof0.4%butanol,TGF-β1inducesanincreaseintheformationofphosphatidylbutanol,auniqueproductcatalyzedbyPLD.TGF-β1alsoinducesanincreaseinphosphatidicacid(PA)levelinA-549andMDCKcells.TGF-β1inducesanincreaseinthelevelsofDAGlabeledwith[^3H]-myristicacidinA-549andMDCKcellsbutnotinMv1Lucells.NoincreaseofDAGwasobservedincellsprelabeledwith[^3H]-arachidonicacid.ThedatapresentedsuggestthatPLDactivationisinvolvedintheTGF-β1-inducedcellgrowthinhibition.

简介：Perforin是主要从事调停的形成毛孔的蛋白质目标T房间死亡并且被细胞毒素的T淋巴细胞(CTL)和自然漂亮房间采用。然而，它是否也在常规CD4+T房间功能起一个作用，仍然保持不清楚。这里，我们报导那在perforin缺乏(PKO)老鼠，CD4+T房间是响应T的hyperproliferative房间受体(TCR)刺激。hyperproliferation的这个特征被改进在房间分割并且在IL-2分泌物伴随。看起来，perforin缺乏不在胸腺怒气和淋巴节点影响T房间开发。在vivo，perforin缺乏导致增加的抗原特定的T房间增长和抗体生产。而且，PKO老鼠更产生试验性的自体免疫的眼色素层炎。探讨分子的机制，我们发现在TCR刺激以后，从PKO老鼠的CD4+T房间显示增加的细胞内部的钙流动并且随后提高抄写因素NFAT1的激活。我们的结果显示perforin在由影响TCR依赖的Ca2+发信号调整CD4+T房间激活和有免疫力的反应起一个否定作用。

简介：混合的系kinase(MLK3)3是被肿瘤坏死因素激活的激活mitogen的蛋白质kinasekinasekinase--伪(TNF-伪)并且明确地在TNF-伪刺激上激活c6月N终端kinase(JNK)。TNF-伪由激活MLK3的机制不被知道。TNF联系受体的因素(TRAF)是被招募到TNF受体的细胞质的结束并且调停的改编者分子，包括JNK的激活下游的发信号。这里，我们报导MLK3与TRAF2，TRAF5和TRAF6联系；然而，仅仅TRAF2能显著地导致MLK3的kinase活动。到TRAF领域并且为到它的C终端一半(氨基酸511-847)的MLK3的TRAF2地图的相互作用领域。与对方一起的内长的TRAF2和响应以一种时间依赖者方式的TNF-伪处理的MLK3伙伴。在MLK3和TRAF2之间的协会调停有绑在MLK3的TRAF2删除异种的MLK3激活和竞争以一种剂量依赖者方式稀释MLK3kinase活动，在TNF-伪处理上。而且MLK3的下游的目标，JNK被TNF-伪以一种TRAF2依赖的方式激活。因此，我们在TRAF2和MLK3之间的直接相互作用为TNF-伪-被要求的数据表演导致了MLK3和它的下游的目标的激活，JNK。

简介：Ionizingradiationisoneofthemosteffectivetoolsincancertherapy.Inapreviousstudy,wereportedthatproteintyrosinekinase(PTK)inhibitorsmodulatetheradiationresponsesinthehumanchronicmyelogenousleukemia(CML)celllineK562.Thereceptortyrosinekinaseinhibitor,genistein,delayedradiation-inducedcelldeath,whilenon-receptertyrosinekinaseinhibitor,herbimycinA(HMA)enhancesradiation-inducedapoptosis.Inthisstudy,wefocusedonthemodulationofradiation-inducedcelldeathbygenisteinandperformedPCR-selectsuppressionsubtractivehybridization(SSH)tounderstanditsmolecularmechanism.Weidentifiedhumanthymidinekinase1(TK1),whichiscellcycleregulatorygeneandconfirmedexpressionofTK1mRNAbyNorthernblotanalysis.ExpressionofTK1mRNAandTK1enzymaticactivitywereparallelintheirincreaseanddecrease.TK1isinvolvedinG1-Sphasetransitionofcellcycleprogression.Incellcycleanalysis,weshowedthatradiationinducedG2arrestinK562cellsbutitwasnotabletosustain.However,theadditionofgenisteintoirradiatedcellssustainedaprolongedG2arrestupto120h.Inaddition,theexpressionofcellcycle-relatedproteins,cyclinAandcyclinB1,providedtheevidencesofG1/SprogressionandG2-arrest,andtheirrelationshipwithTK1incellstreatedwithradiationandgenistein.TheseresultssuggestthattheactivationofTK1maybecriticaltomodulatetheradiation-inducedcelldeathandcellcycleprogressioninirradiatedK562cells.

简介：LKB1是直接激活精力传感器的serine/threoninekinase响应bioenergetic应力的激活安培的蛋白质kinase(AMPK)，并且主要充当控制房间极性和增长的肿瘤suppressor。尽管LKB1包括胸腺和怒气在多重纸巾被表示，它在T房间开发和功能的角色仍然保持未知。这里，我们证明LKB1的那T-cell-specific删除导致了双positive(DP)的减少的幸存thymocytes和CD4和CD8的损害产生单人赛积极的thymocytes。LKB1的混乱不仅阻止了AMPK的激活而且损害了anti-apoptotic蛋白质Bcl-XL的表示。重要地，任何一个Bcl-XL的宫外的表示或组成地活跃的AMPK异种显著地救了DPthymocytes免于LKB1导致缺乏的房间死亡。而且，组成地活跃的AMPK异种的宫外的表示被发现在LKB1缺乏的DPthymocytes恢复Bcl-XL的表示。这些调查结果通过AMPK激活和Bcl-XL表示的规定为DPthymocytes的幸存作为一个关键因素识别LKB1。

简介：现在的学习试图定义postsynaptic的角色在多巴胺(DA)的规定的密度(PSD)-95受体功能。我们发现PSD-95身体上在co-transfectedHEK-293房间与D1或D2DA受体联系。DA受体的刺激以一种时间依赖者方式改变了在D1受体和PSD-95之间的协会。功能的试金显示PSD-95合作表示没影响D1刺激受体的营地生产，Gs蛋白质激活或受体不敏感性。然而，PSD-95由支持受体再循环加速了使内在化的膜受体的恢复，因此导致使内在化的D1受体的提高的促进感受性。我们的结果提供新奇机制因为调整再循环那的DA受体可以在postsynapticDA功能的调整和synapticneuroplasticity起一个重要作用。

简介：小道，肿瘤坏死因素相关的导致apoptosisligand，是一个新奇有势力通过房间表面死亡受体Trail-R1和Trail-R2的激活的房间死亡小径的内长的使活跃之物。它的角色象在导致激活的房间死亡(AICD)的FasL一样，在免疫系统被表明了。然而，小道的机制导致了apoptosis遗体不清楚。在这份报告，重组体小道蛋白质被表示并且净化。导致apoptosis活动和JurkatT房间上的重组体小道的规定机制是探索试管内。Trypan蓝排除试金证明重组体小道蛋白质活跃地以一种剂量依赖者方式杀死了JurkatT房间。在JurkatT房间的导致小道的apoptosis被Bcl-2显著地在Bcl-2基因transfected房间在表示上减少。有PMA(phorbol12十四酸盐13醋酸盐)的处理，PKC使活跃之物，在JurkatT房间的压制的导致小道的apoptosis。由PMA的apoptosis的抑制被预告的处理与二度废除，一个PKC禁止者。总起来说，Bcl-2在表示上和PMA激活PKC，这被建议活跃地下面调整在JurkatT的调停小道的apoptosis房间。

简介：Amurinemacrophage-likecelllineJ774,acquired,inresponsetoLPS,anabilitytokilltumornecrosisfactor(TNF)-insensitivetargetP815mastocytomacellswhereasanothercellline,P388D1didnot,LPStriggeredsignalingmechanismsbetweenthetwocelllineswerecomparedwithanaimtoinquireaboutthepossiblenatureoftheabove-mentioneddifference,TheresultswhowedthattwocelllinesrespondtoLPS-treatmentbyparallelactivationofbothphospholipasesCandA2(PLCandPLA2)toapproximatelythesameextent.ThemaximumresponseoftothenzymesofJ774cellswasnotedwithin10minthetreatmentwhereasthatofP388D1cellsrequiredmorethan20min,TheotherpropertiesofLPS-responsiveenzymesstudiedweresimilarbetweentwocelllines,includingActivationofPLCandPLA2andPKCinmacrophagesbyLPS.Ca2+augmentationofenzymeactivation,participationofguaninenucleotidebinding(G)proteinsintheinitialactivationpreocesses,andinhibitionofenzymeactivationbythepriortreatmentofcellswithcholeraorpertussistoxinsetc.Moreover,LPS-triggeredactivationofPLCandPLA2wasfoundtobefollowedbytheincreaseofPKCactivitiesinbothcelllines.Inspiteofthesesimilarities.J774cellspossessedbothbasicandacidicformsofPKCactivities,whileP388D1cellsownedonlyPKCofbasicform,Nevertheless,thequestionwhyJ774cellsbutnotP388D1cells,canacquirethetumoricidalactivity,aganistP815,cellsfollowingLPStreatmentrematinstobeanswered.

简介：Usingtwo-colourflowcytometry＞200antibodiessubmittedtothe8thInternationalWorkshopofHumanLeukocyteDifferentiationAntigens(HLDA8)havebeenanalyzedfortheirreactivitywithrestingandactivatedCD203c+basophils.Fourantibodieseithernon-reactiveorweaklyreactivewithrestingbasophilsexhibitedanincreasedreactivitywithbasophilsactivatedbyanti-IgE-mediatedcross-linkingofthehighaffinityIgEreceptor(FcεRI).TheseincludeantibodiesagainstCD164(WS-80160,cloneN6B6andWS-80162,clone67D2),aswellastworeagentswithpreviouslyunknownspecificitiesthatwereidentifiedasCD13(WS-80274,cloneA8)andCD107a(WS-80280,cloneE63-880).Theactivationpatternsfollowedeitherthe'CD203c-like'or'CD63-like'activationprofile.TheCD203cprofileischaracterizedbyarapidandsignificantupregulation(ofCD13,CD164,andCD203c),reachingmaximumlevelsafter5-15minofstimulation.ThePhosphoinositide-3-kinase(PI3K)-specificinhibitorWortmannininhibitedtheupregulationofthesemarkerswhereas12-O-tetradecanoyl-phorbol-13-acetate(TPA)inducedarapidandFcεRI-independentupregulationwithin1-2min.IntheCD63profile,maximumupregulation(ofCD63andCD107a)wasdetectedonlyafter20-40min,andupregulationbyTPAreachedmaximumlevelsafter60min.Insummary,ourdataidentifyCD13,CD107a,andCD164asnovelbasophil-activationantigens.Basedontimekineticsofupregulation,wehypothesizethatmoleculesofthe'CD203cgroup'andthe'CD63group'arelinkedtotwodifferentmechanismsofbasophilactivation.

简介：Amurinemacrophage-likecellline,J774,acquried,inresponsetoLPS,anabilitytokilltumornecrosisfactor（TNF）-insensitivetargetP815mastocytomacells,whereasanothercellline,P388D1,didnot.LPS-triggeredsignalingmechanismsbetweenthetwocelllineswerecomparedwithanaimtoinquireaboutthepossiblenatureoftheabove-mentioneddifference.TheresultsshowedthattwocelllinesrespondtoLPS-treatmentbyparallelactivationofbothphospholipasesCandA2（PLCandPLA2）toapproximatelythesameextent.ThemaximumresponseofbothenzymesofJ774cellswasnotedwithin10minofthetreatment,whereasthatofP388D1cellsrequiredmorethan20min.TheotherpropertiesofLPS-responsiveenzymesstudiedweresimilarbetweentwocelllines,ineludingActivationofPLCandPLA2andPKCinmacrophagesbyLPSCa2+augmentationofenzymeactivation,participationofguaninenucleotidebinding（G）proteinsintheinitialactivationprocesses,andinhibitionofenzymeactivationbythepriortreatmentofcellswithcholeraorpartussistoxinsetc.Moreover,LPS-triggeredactivationofPLCandPLA2wasfoundtobefollowedbytheincreaseofPKCactivitiesinbothcelllines.Inspiteofthesesimilarities,J774cellspossessedbothbasicandacidicformsofPKCactivities,whileP388D1cellsownedonlyPKCofbasicform.Nevertheless,thequestionwhyJ774cells,butnotP388D1cells,canacquirethetumoricidalactiyity,aganistP815cellsfollowingLPS-treatmentremainstobeanswered.

简介：OverexpressionandactivationofHER-2/neu(alsoknownasc-erbB-2),aproto-oncogene,wasfoundinabout30%ofhumanbreastcancers,promotingcancergrowthandmakingcancercellsresistanttochemo-andradio-therapy.Wild-typep53iscrucialinregulatingcellgrowthandapoptosisandisfoundtobemutatedordeletedin60-70%ofhumancancers.Andsomecancerswithawild-typep53donothavenormalp53function,suggestingthatitisimplicatedinacomplexprocessregulatedbymanyfactors.Inthepresentstudy,weshowedthattheoverexpressionofHER-2/neucoulddecreasetheamountofwild-typep53proteinviaactivatingPI3Kpathway,aswellasinducingMDM2nucleartranslocationinMCF7humanbreastcancercells.BlockageofPI3KpathwaywithitsspecificinhibitorLY294002causedG1-Sphasearrest,decreasedcellgrowthrateandincreasedchemo-andradio-therapeuticsensitivityinMCF7cellsexpressingwild-typep53.However,itdidnotincreasethesensitivitytoadriamycininMDA-MB-453breastcancercellscontainingmutantp53.OurstudyindicatesthatblockingPI3KpathwayactivationmediatedbyHER-2/neuoverexpressionmaybeusefulinthetreatmentofbreasttumorswithHER-2/neuoverexpressionandwild-typep53.