OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP0OMIMUniSTS0*602233LinksAPOPTOTICPROTEASEACTIVATINGFACTOR1APAF1Genemaplocus12q23TEXTCLONINGFromHeLacellcytosolZouetal(1997)purifiedandclonedacDNAofAPAF1a130kDproteinthatparticipatesinthecytochromec(123970)dependentactivationofcaspase3(CASP3600636)TheNH2terminal85aminoacidsofAPAF1show21%identitytotheNH2terminalprodomainoftheCeleganscaspaseCED3Thenext320aminoacidsshow22%identitytoCED4aproteinthatisbelievedtoinitiateapoptosisinCelegansTheCOOHterminalregionofAPAF1comprisesmultipleWDrepeatswhichareproposedtomediateproteinproteininteractionsCytochromecbindstoAPAF1aneventthatmaytriggertheactivationofCASP3leadingtoapoptosisInanRTPCRscreenofvariousnormalandtumorcelllinesandtissuesHahnetal(1999)identified3variantsofAPAF1TheseformsvariedinlengthbutsequenceanalysisindicatedthateachcontainedallofthefunctionaldomainspreviouslycharacterizedbyZouetal(1997)GENEFUNCTIONActivationofprocaspase9(CASP9602234)byAPAF1inthecytochromec/dATPdependentpathwayrequiresproteolyticcleavagetogeneratethematurecaspasemoleculeSrinivasulaetal(1998)showedthatdeletionoftheAPAF1WD40repeatsmakesAPAF1constitutivelyactiveandcapableofprocessingprocaspase9independentofcytochromecanddATPAPAF1mediatedprocessingofprocaspase9occursatasp315byanintrinsicautocatalyticactivityofprocaspase9itselfSrinivasulaetal(1998)providedevidencethatAPAF1canformoligomersandmayfacilitateprocaspase9autoactivationbyoligomerizingitsprecursormoleculesOnceactivatedcaspase9caninitiateabiochemicalcascadeinvolvingthedownstreamexecutionerscaspase36and7MetastaticmelanomaisadeadlycancerthatfailstorespondtoconventionalchemotherapyMutationsinp53(191170)oftenoccurinaggressiveandchemoresistantcancersbutarerarelyobservedinmelanomaSoengasetal(2001)showedthatmetastaticmelanomasoftenloseAPAF1LossofAPAF1expressionwasaccompaniedbyalleliclossinmetastaticmelanomasbutcouldberecoveredinmelanomacelllinesbytreatmentwiththemethylationinhibitor5aza2primedeoxycytidine(5aza2dC)APAF1negativemelanomaswereinvariablychemoresistantandwereunabletoexecuteatypicalapoptoticprograminresponsetop53activationRestoringphysiologiclevelsofAPAF1throughgenetransferor5aza2dCtreatmentmarkedlyenhancedchemosensitivityandrescuedtheapoptoticdefectsassociatedwithAPAF1lossSoengasetal(2001)concludedthatAPAF1isinactivatedinmetastaticmelanomasleadingtodefectsintheexecutionofapoptoticcelldeathRoblesetal(2001)identifiedaclassicp53responsiveelementupstreamoftheAPAF1transcriptionstartsitethatboundp53andinducedAPAF1geneexpressionApoptosisinalymphoblastoidcelllinecausedbyDNAdamageduetoexposuretoionizingradiationortodoxorubicininducedAPAF1mRNAandproteinexpressionandwasstrictlydependentonwildtypep53functionRoblesetal(2001)concludedthatAPAF1isanessentialdownstreameffectorofp53mediatedapoptosisFortinetal(2001)identified2p53consensusbindingsitesinthemouseApaf1promoterByelectrophoreticmobilityshiftassaysandtransienttransfectionsofApaf1promoterreporterconstructsintomouseneuronalcellstheydemonstratedthatbothsiteswereutilizedbyp53PrimaryculturesofApaf1deficientneuronsweresignificantlyprotectedfromp53inducedapoptosisFurukawaetal(2002)identifiedanE2F1(189971)bindingelementwithinthepromoterregionofhumanAPAF1andconfirmedbindinginachromatinimmunoprecipitationassayTheyfoundthatE2F1inducedapoptosiswasaccompaniedbycaspase9activationandenhancedexpressionofAPAF1withoutthecytosolicaccumulationofcytochromecOverexpressionofAPAF1resultedindirectactivationofcaspase9withoutmitochondrialdamageandinitiatedacaspasecascadeMarsdenetal(2002)establishedthatthecelldeathpathwaycontrolledbyBCL2(151430)doesnotrequirecaspase9oritsactivatorAPAF1InkeepingwiththeirevidencethatneitherisrequiredforhematopoietichomeostasisinwhichtheBCL2familyhasmajorrolesdeletionofthymocyteswithselfreactivitydependsonBIM(603827)butnotonAPAF1BecauseapoptosiswasatmostslightlydelayedbytheabsenceofAPAF1orcaspase9Marsdenetal(2002)concludedthattheapoptosomeisnotanessentialtriggerforapoptosisbutisratheramachineforamplifyingthecaspasecascadeTheyfoundthatBCL2overexpressionincreasedlymphocytenumbersinmiceandinhibitedmanyapoptoticstimulibuttheabsenceofAPAF1andcaspase9didnotCaspaseactivitywasstilldiscernibleincellslackingAPAF1orcaspase9andapotentcaspaseantagonistbothinhibitedapoptosisandretardedcytochromecreleaseMarsdenetal(2002)concludedthatBCL2regulatesacaspaseactivationprogramindependentlyofthecytochromec/APAF1/caspase9apoptosomewhichseemstoamplifyratherthaninitiatethecaspasecascadeBIOCHEMICALFEATURESCrystalStructureRiedletal(2005)reportedthe22angstromcrystalstructureofanADPboundWD40deletedAPAF1whichrevealedthemolecularmechanismBywhichAPAF1existsinaninactivestatebeforeATPbindingTheNterminalcaspaserecruitmentdomainpacksagainsta3layeredalpha/betafoldashorthelicalmotifandawingedhelixdomainresultingintheburialoftheCASP9(602234)bindinginterfaceThedeeplyburiedADPmoleculeservesasanorganizingcentertostrengtheninteractionsbetweenthese4adjoiningdomainsthuslockingAPAF1inaninactiveconformationAPAF1bindstoandhydrolyzesATP/dATPandtheiranalogsRiedletal(2005)concludedthatthebindingandhydrolysisofnucleotidesseemtodriveconformationalchangesthatareessentialfortheformationoftheapoptosomeandtheactivationofCASP9MAPPINGByfluorescenceinsituhybridizationKimetal(1999)mappedtheAPAF1genetochromosome12q23MOLECULARGENETICSHarlanetal(2006)studiedAPAF1variantstodeterminemolecularphenotypesusinganinvitroreconstructionoftheapoptosomecomplexinwhichApaf1activatescaspase9andthusinitiatesacascadeofproteolyticeventsleadingtoapoptoticdestructionofthecellCellularphenotypesweremeasuredusingayeastheterologousexpressionassayHumanvariantsencodedbyAPAF1allelesthatsegregatewithmajordepressioninfamilieslinkedtochromosome12q(MDD1608520)demonstratedacommongainoffunctionphenotypeinbothassaysystemsIncontrastotherAPAF1variantsshowedneutralorlossoffunctionphenotypesHarlanetal(2006)concludedthatdepressionassociatedalleleshaveacommonphenotypethatisdistinctfromthatofnonassociatedvariantssuggestinganetiologicroleforenhancedapoptosisinmajordepressionANIMALMODELThecytosolicproteinAPAF1humanhomologofCelegansCED4participatesintheCASP9dependentactivationofCASP3inthegeneralapoptoticpathwayCecconietal(1998)generatedbygenetrapanullalleleofthemurineApaf1Homozygousmutantsdiedatembryonicday165TheirphenotypeincludedseverecraniofacialmalformationsbrainovergrowthpersistenceoftheinterdigitalwebsanddramaticalterationsofthelensandretinaHomozygousembryonicfibroblastsexhibitedreducedresponsetovariousapoptoticstimuliInsituimmunodetectionshowedthattheabsenceofApaf1proteinpreventedtheactivationofCasp3invivoInagreementwiththereportedfunctionofCED4inCelegansthisphenotypecanbecorrelatedwithadefectofapoptosisCecconietal(1998)suggestedthatApaf1isessentialforCasp3activationinembryonicbrainandisakeyregulatorofdevelopmentalprogrammedcelldeathinmammalsYoshidaetal(1998)alsoproducedApaf1deficientmicewhichexhibitedreducedapoptosisinthebrainandstrikingcraniofacialabnormalitieswithhyperproliferationofneuronalcellsApaf1deficientcellswereresistanttoavarietyofapoptoticstimuliandtheprocessingofcaspases23and8wasimpairedHoweverbothApaf1/thymocytesandactivatedTlymphocytesweresensitivetoFasinducedkillingshowingthatFasmediatedapoptosisinthesecellsisindependentofApaf1ThesedataindicatedthatApaf1playsacentralroleinthecommoneventsofmitochondriadependentapoptosisinmostdeathpathwaysandthatthisroleiscriticalfornormaldevelopmentHonarpouretal(2000)extendedpreviousfindingsofperinatalmortalityandexencephalyinApaf1/micebyshowingthatneurogenesiswasaberrantatboththeneuralprogenitorandthematureneuronstageinthesemiceTheynotedthat5%ofApaf1mutantmicesurvivedtoadulthoodwithoutbrainpathologybuttheirmalegermcelldevelopmentexhibitedspermatogoniadegenerationsimilartothatobservedinBax(600040)deficientmiceormiceoverexpressingBcl2(151430)orBclxl(BCL2L1600039)Honarpouretal(2000)concludedthatcompensatoryalternativeapoptoticpathwaysexistintheabsenceofcytochromecandcaspase3mediatedapoptosisinbraindevelopmentbutthesepathwaysareessentialforspermatogenesisThe'forebrainovergrowth'mutation(fog)inmicewasoriginallydescribedasaspontaneousautosomalrecessivemutationmappingtochromosome10thatproducesforebraindefectsfacialdefectsandspinabifidaBecauseofitsphenotypicresemblancetoapoptoticproteaseactivatingfactor1(Apaf1)knockoutmiceHonarpouretal(2001)investigatedthepossibilitythatthefogmutationisintheApaf1geneTheyshowedthatfogmutantmicelackApaf1activityandthatApaf1mRNAisaberrantlyprocessedresultingingreatlyreducedexpressionlevelsofnormalmRNAThesefindingsstronglysuggestedthatthefogmutationisahypomorphicApaf1defectandimplicatedneuralprogenitorcelldeathinthepathogenesisofspinabifidaBecauseacompletedeficiencyinApaf1usuallyresultsinperinatallethalityandfog/foghomozygousmicemorereadilysurviveintoadulthoodthesemutantsserveasavaluablemodelwithwhichapoptoticcelldeathcanbestudiedinvivoREFERENCES1CecconiFAlvarezBoladoGMeyerBIRothKAGrussPApaf1(CED4homolog)regulatesprogrammedcelldeathinmammaliandevelopmentCell947277371998PubMedID97533202FortinACreganSPMacLaurinJGKushwahaNHickmanESThompsonCSHakimAAlbertPRCecconiFHelinKParkDSSlackRSAPAF1isakeytranscriptionaltargetforp53intheregulationofneuronalcelldeathJCellBiol1552072162001PubMedID115917303FurukawaYNishimuraNFurukawaYSatohMEndoHIwaseSYamadaHMatsudaMKanoYNakamuraMApaf1isamediatorofE2F1inducedapoptosisJBiolChem27739760397682002PubMedID121492444HahnCHirschBJahnkeDDurkopHSteinHThreenewtypesofApaf1inmammaliancellsBiochemBiophysResCommun2617467491999PubMedID104414965HarlanJChenYGubbinsEMuellerRRochJMWalterKLakeMOlsenTMetzgerPDorwinSLadrorUEganDAand17othersVariantsinApaf1segregatingwithmajordepressionpromoteapoptosomefunctionMolecPsychiat11768520066HonarpourNDuCRichardsonJAHammerREWangXHerzJAdultApaf1deficientmiceexhibitmaleinfertilityDevBiol2182482582000PubMedID106567677HonarpourNGilbertSLLahnBTWangXHerzJApaf1deficiencyandneuraltubeclosuredefectsarefoundinfogmiceProcNatAcadSci98968396872001PubMedID115049438KimHJungYKKwonYKParkSHAssignmentofapoptoticproteaseactivatingfactor1gene(APAF1)tohumanchromosomeband12q23byfluorescenceinsituhybridizationCytogenetCellGenet872522531999PubMedID107026829MarsdenVSO'ConnorLO'ReillyLASilkeJMetcalfDEkertPGHuangDCSCecconiFKuidaKTomaselliKJRoySNicholsonDWVauxDLBouilletPAdamsJMStrasserAApoptosisinitiatedbyBcl2regulatedcaspaseactivationindependentlyofthecytochromec/Apaf1/caspase9apoptosomeNature4196346372002PubMedID1237498310RiedlSJLiWChaoYSchwarzenbacherRShiYStructureoftheapoptoticproteaseactivatingfactor1boundtoADPNature4349269332005PubMedID1582996911RoblesAIBemmelsNAForakerABHarrisCCAPAF1isatranscriptionaltargetofp53inDNAdamageinducedapoptosisCancerRes61666066642001PubMedID1155953012SoengasMSCapodieciPPolskyDMoraJEstellerMOpitzArayaXMcCombieRHermanJGGeraldWLLazebnikYACordonCardoCLoweSWInactivationoftheapoptosiseffectorApaf1inmalignantmelanomaNature4092072112001PubMedID1119664613SrinivasulaSMAhmadMFernandesAlnemriTAlnemriESAutoactivationofprocaspase9byApaf1mediatedoligomerizationMolecCell19499571998PubMedID965157814YoshidaHKongYYYoshidaREliaAJHakemAHakemRPenningerJMMakTWApaf1isrequiredformitochondrialpathwaysofapoptosisandbraindevelopmentCell947397501998PubMedID975332115ZouHHenzelWJLiuXLutschgAWangXAPAF1ahumanproteinhomologoustoCelegansCED4participatesincytochromecdependentactivationofcaspase3Cell904054131997PubMedID9267021CONTRIBUTORSJohnLoganBlackIIIupdated6/2/2006AdaHamoshupdated9/19/2005PatriciaAHartzupdated12/17/2002AdaHamoshupdated10/2/2002VictorAMcKusickupdated5/13/2002PaulJConverseupdated4/24/2002PatriciaAHartzupdated4/9/2002AdaHamoshupdated1/9/2001CarolABocchiniupdated10/13/2000StylianosEAntonarakisupdated9/30/1998StylianosEAntonarakisupdated8/3/1998CREATIONDATEStylianosEAntonarakis1/7/1998EDITHISTORYwwang6/7/2006terry6/2/2006alopez9/21/2005terry9/19/2005mgross1/3/2003terry12/17/2002alopez10/18/2002alopez10/18/2002alopez10/2/2002alopez5/21/2002terry5/13/2002mgross4/24/2002mgross4/24/2002carol4/9/2002mgross1/10/2001terry1/9/2001terry10/16/2000carol10/13/2000alopez2/5/1999carol9/30/1998carol8/4/1998terry8/3/1998carol3/21/1998carol1/8/1998Copyright©19662007JohnsHopkinsUniversityDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardDisclaimerWritetotheHelpDeskPrivacyPolicyNCBINLMNIH