Over1,000papersandreviewshavebeenwrittenabouttheroleofceramideintheproductionofprogrammedcelldeathorapoptosis.Ceramideisasphingosine-basedlipid-signalingmoleculeinvolvedintheregulationofcellulardifferentiation,proliferation,andapoptosis.Thisdiagramrepresentssomeofthecurrentunderstandingofthecascadesthatcoupleceramidetospecificsignalingpathways.Thesecascadesillustratethatceramidecanbeagrowthstimulusorproapototicsignal.Theultimateceramideactionisdeterminedwithinthecontextofotherstimuliandbythesubcellulartopologyofitsproductionandiscell-typespecific.Thereare2formsofsphingomyelinase,acid(acid-sphingomyelinase:A-SMase)andneutral(neutral-sphingomyelinaseN-SMase),thatcanproduceceramide.TNF-alphacanstimulateeitherformofsphingomyelinaseascanother“deathreceptors”.DifferentdomanisofTNF-alphastimulatethedifferentSmases.N-SMasestimulationisenhancedbythereceptorforactivated-Ckinase1(RACK1).TheactivityofeachformisdependentonthelocalintracellularpH.Intheillustrationtheformsareseperatedtoreduceconfusionhoweverceramideproducedbyeithermethodcanstimulateeithercascadedependingonthepresenceofspecificco-factorsandactivators.A-SMasehasbeenrecognizedasoneoftherequiredmoleculestomediateproapoptoticsignallingincelldeathinducedbyadiversearrayofstressessuchasH2O2,Heat,UVexposureandRADIation.ROSgenerationinmitochondriaactivatescaspase-3viacooperationofcytochromec,Aifandcaspase-9andstimulatesorincreasesceramidegenerationthroughA-SMaseinaproaptoticactivationcycle.Caspase-3furtherincreasesitsownactivationbyproteolyticallycleavingceramideinhibitedcatalasewhichisaninhibitorofROSgeneration.Ceramide-activatedproteinkinase(CARK)alsoknownasKinaseSupressorofRAS(KSR)activityisinsomecasestheswitchpointinthebalancebetweenproapoptoticandantiapoptoticsignalsandisalsocell-typespecific.InendothelialcellsforexampletheactivationofKSRisrequiredforapoptosis.IncontrastinepithelialcellsactivationofKSRisrequiredforcellproliferation.AnadditionalswitchpointistheavailABIlityofBadinthecell.ActivationofKSRleadstofurthermitocondrialstimulationorassociationwithRASandactivationoftheRaf1cascadeleadingtoproliferationordifferentiation.

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