简介:AktandBcl-xLbothpromoteresistancetoapoptosis.AcomparisonofAkt-andBcl-xL-dependentcellsurvivalwasundertaken.ExpressionofconstitutivelyactiveAktallowscellstosurviveforprolongedperiodsintheabsenceofgrowthfactors.ThissurvivalcorrelateswiththeexpressionlevelofactivatedAktandiscomparableinmagnitudetotheprotectionprovidedbytheanti-apoptoticgeneBcl-xL.Althoughbothgenespreventcelldeath,Akt-protectedcellscanbedistinguishedfromBcl-xL-protectedcellsonthebasisofincreasedglucosetransporterexpression,glycolyticactivity,mitochondrialpotential,andcellsize.Inaddition,Akt-expressingcellsrequirehighlevelsofextracellularnutrientstosupportcellsurvival.In
简介:PTEN,phosphatidylinositol-3-kinase/AKT小径的一个否定管理者,是胰岛素发信号的一个重要调节的人。决定胰腺的Pten的新陈代谢的函数,我们产生了胰特定的Pten大美人(PPKO)鼠标。PPKO老鼠扩大了胰并且提高了acinar房间的增长。他们也展出了低血糖症,hypoinsulinemia,和改变的氨基的新陈代谢。尤其是,PPKO老鼠证明streptozotocin(STZ)的推迟的发作导致了糖尿病,到high-fat-diet(HFD)的偏导性的抵抗导致了糖尿病。在PPKO老鼠为抵抗调查机制到导致HFD的多糖症,我们在主要胰岛素应答的纸巾评估了AKTphosphorylation:肝,肌肉,和脂肪。我们发现在胰的Pten损失引起在肝发信号的AKT的举起。AKT和它的下游的底层GSK3尾的phosphorylation在PPKO老鼠的肝被增加,当没有Pten等位基因的可检测的切除,PTEN水平在PPKO老鼠的肝被减少时。戏剧性地揭示的Proteomics分析减少了在PPKO老鼠的肝78-kDa铺平调整葡萄糖的蛋白质(GRP78),它可以也贡献用HFD喂的PPKO老鼠的更低的血葡萄糖水平。一起,我们的调查结果在新陈代谢的规定在肝揭示新奇回答到胰腺的缺点,把一种新尺寸加到理解糖尿病抵抗。
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:ApoptosisproducedinBcellsthroughFas(APO-1,CD95)triggeringisregulatedbysignalsderivedfromothersurfacereceptors:CD40engagementproducesupregulationofFasexpressionandmarkedsusceptibilitytoFas-inducedcelldeath,whereasantigenreceptorengagement,orIL-4Rengagement,inhibitsFaskillingandinsodoinginducesastateofFas-resistance,eveninotherwisesensitive,CD40-stimulatedtargets.SurfaceimmunoglobulinandIL-4RutilizeatleastpartiallydistinctpathwaystoproduceFas-resistancethatdifferentiallydependonPKCandSTAT6,respectively.Further,surfaceimmunoglobulinsignalingforinducibleFas-resistancebypassesBtk,requiresNF-κB,andentailsnewmacromolecularsynthesis.TerminaleffectorsofBcellFas-resistanceincludetheknownanti-apoptoticgeneproducts,Bcl-XLandFLIP,andanovelanti-apoptoticgenethatencodesFAIM(FasApoptosisInhibitoryMolecule).faimwasidentifiedbydifferentialdisplayandexistsintwoalternativelysplicedforms;faim-Sisbroadlyexpressed,butfaim-Lexpressionistissue-specific.TheFAIMsequenceishighlyevolutionarilyconserved,suggestinganimportantroleforthismoleculethroughoutphylogeny.InducibleresistancetoFaskillingishypothesizedtoprotectforeignantigen-specificBcellsduringpotentiallyhazardousinteractionswithFasL-bearingTcells,whereasautoreactiveBcellsfailtobecomeFas-resistantandaredeletedviaFas-dependentcytotoxicity.InadvertentoraberrantacquisitionofFas-resistancemaypermitautoreactiveBcellstoescapeFasdeletion,andmalignantlymphocytestoimpedeanti-tumorimmunity.
简介:<正>ThesusceptibilityofprimaryBcellstoFas(APO-1,CD95)-mediatedapoptosisisregulatedbysignalsderivedfromadditionalsurfacereceptors.CD40engagementproducesupregulationofFasexpressionandinducesmarkedsensitivitytoFas-inducedcelldeath,whereasBcellantigenreceptor(BCR)engagementinhibitsFaskillingandtherebyproducesFas-resistance,eveninotherwisesusceptible,CD40-stimulatedtargets.BCRsignalingforinducibleFas-resistancedevelopsoveraperiodof12hoursanddependson
简介:<正>WeandothershavefirmlyestablishedthatsurfaceIgMreceptor(sIgM-R)crosslinkingwithantibodiestotheiheavychain(anti-i)leadstogrowtharrestandapoptosisinaseriesofwellcharacterizedB-celllymphomas.Thisrequiresablationofc-Mycproteinexpressionandtheconcomitantinductionofthecyclin-dependent-kinaseinhibitor,p27Kip1.Thesignalingmechanismsregulatingc-Mycandp27Kip1proteinexpressionarepoorlyunderstood.However,werecentlyestablishedthatsIgM-Rmediateddown-modulationofthePI-3Kpathwaydirectlyaffectedc-Mycandp27Kip1expressionandaccuratelypredictedgrowtharrest