OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP0OMIMUniSTS0*600253LinksARYLHYDROCARBONRECEPTORAHRGenemaplocus7p15TEXTDESCRIPTIONHalogenatedaromatichydrocarbonsrepresentedby2378tetrachlorodibenzopdioxin(TCDD)areenvironmentalpollutantsthatareproducedbyminorsidereactionsinchemicalmanufacturingprocessesandbycombustionofwastematerialsThesechemicalscausepotentandpleiotropictoxicityincludingteratogenesisimmunesuppressionepithelialdisordersandtumorproductioninexperimentalanimalsAtthemolecularlevelaldehydedehydrogenasequinonereductaseandvariousdrugmetabolizingenzymesareinducedbythechemicalsinsomeculturedcellsandsometissuesofexperimentalanimalsAllthesebiologiceffectsarethoughttobemediatedbyanintracellulararylhydrocarbonreceptor(AHR)CLONINGEmaetal(1994)isolatedhumancDNAfortheAHRgeneusingmousecDNAasalabeledprobeThededucedprimarystructureofhumanAHRshowedanoverallaminoacidsimilarityof725%withthatofthemousecounterpartProteinencodedbytheAHRcDNAboundtheinducerTCDDwithahighaffinityina9ScomplexformGENEFUNCTIONAheterodimerofthedioxinreceptor(AHR)andARNT(126110)whicharebasichelixloophelix/PASfamilytranscriptionfactorsmediatesmostofthetoxiceffectsofdioxinsOhtakeetal(2003)demonstratedthattheagonistactivatedAHR/ARNTheterodimerdirectlyassociateswiththeestrogenreceptorsERalpha(133430)andERbeta(601663)Theyshowedthatthisassociationresultsintherecruitmentofunligandedestrogenreceptorandthecoactivatorp300(602700)toestrogenresponsivegenepromotersleadingtoactivationoftranscriptionandestrogeniceffectsThefunctionofligandedestrogenreceptorwasfoundtobeattenuatedEstrogenicactionsofAHRagonistsweredetectedinwildtypeovariectomizedmouseuteributwereabsentinAhr/orEralpha/ovariectomizedmiceOhtakeetal(2003)concludedthattheirfindingssuggestanovelmechanismbywhichestrogenreceptormediatedestrogensignalingismodulatedbyacoregulatorylikefunctionofactivatedAHR/ARNTgivingrisetoadverseestrogenrelatedactionsofdioxintypeenvironmentalcontaminantsOhtakeetal(2007)characterizedafatsolubleliganddependentubiquitinligasecomplexinhumancelllinesinwhichAHRisintegratedasacomponentofanovelcullin4B(300304)ubiquitinligasecomplexCUL4B(AHR)ComplexassemblyandubiquitinligaseactivityofCUL4B(AHR)invitroandinvivoaredependentontheAHRligandIntheCUL4B(AHR)complexligandactivatedAHRactsasasubstratespecificadaptorcomponentthattargetssexsteroidreceptorsfordegradationOhtakeetal(2007)concludedthattheirfindingsuncoveredafunctionforAHRasanatypicalcomponentoftheubiquitinligasecomplexanddemonstratedanongenomicsignalingpathwayinwhichfatsolubleligandsregulatetargetproteinselectivedegradationthroughaubiquitinligasecomplexMAPPINGByfluorescenceinsituhybridizationandbyDNAblothybridizationusinghuman/mouseorhuman/ChinesehamsterhybridcellDNAsEmaetal(1994)assignedtheAHRgeneto7p21ByuseofPCRanalysisofsomaticcellhybridsandfluorescenceinsituhybridizationofmetaphasecellsLeBeauetal(1994)localizedtheAHRgeneto7p21p15Mickaetal(1997)localizedtheAHRgeneto7p15usingfluorescenceinsituhybridizationPerforminglinkageanalysisina3generationfamilytheyshowedwithgoodprobabilitythatthehighCYP1A1(108330)inducibilityphenotypesegregateswiththe7p15regionMOLECULARGENETICSMickaetal(1997)sequenced93nucleotides(correspondingto31aminoacids)ofexon9ofthehumanAHRgenewhichistheregioncorrespondingtothatcontainingthemouseala375tovalpolymorphismandfoundnonucleotidedifferencesval381waspresentinall5individualsexamined2ofwhomshowed'high'and3ofwhom'low'CYP1A1inducibilityANIMALMODELTodeterminewhetherthearylhydrocarbonreceptorplaysaroleinmodulatingcarcinogenesisthroughtheinductionofxenobioticmetabolizingenzymesShimizuetal(2000)studiedAhrdeficientmiceexposedtobenzo(a)pyreneawidelydistributedenvironmentalcarcinogenTheyfoundthatthecarcinogenicityofthisagentwaslostinAhrdeficientmiceShimizuetal(2000)concludedthatthecarcinogenicactionofbenzo(a)pyrenecanbedeterminedprimarilybyAHRatranscriptionalregulatorofthegeneforCYP1A1Polycyclicaromatichydrocarbons(PAHs)aretoxicchemicalsreleasedintotheenvironmentbyfossilfuelcombustionOocytedestructionandovarianfailureoccurinPAHtreatedmiceandcigarettesmokingcausesearlymenopauseinwomenInmanycellsPAHsactivatetheAHRamemberofthePerArntSimfamilyoftranscriptionfactorsTheAHRisalsoactivatedbydioxinoneofthemostintensivelystudiedenvironmentalcontaminantsMatikainenetal(2001)demonstratedthatanexposureofmicetoPAHsinducestheexpressionofBax(600040)inoocytesfollowedbyapoptosisOvariandamagecausedbyPAHsispreventedbyAhrorBaxinactivationOocytesmicroinjectedwithaBaxpromoterreporterconstructshowAhrdependenttranscriptionalactivationafterPAHbutnotdioxintreatmentconsistentwithfindingsthatdioxinisnotcytotoxictooocytesThisdifferenceintheactionofPAHsversusdioxinisconveyedbyasinglebasepairflankingeachAhrresponseelementintheBaxpromoterOocytesinhumanovarianbiopsiesgraftedintoimmunodeficientmicealsoaccumulatedBaxandunderwentapoptosisafterPAHexposureinvivoThusMatikainenetal(2001)concludedthatAHRdrivenBaxtranscriptionisanovelandevolutionarilyconservedcelldeathsignalingpathwayresponsibleforenvironmentaltoxicantinducedovarianfailureEnvironmentalpollutantsnotablypolychlorinateddioxinsandbiphenylsrepresentwellcharacterizedAHRligandsThedioxin/AHRfunctionsasaligandactivatedtranscriptionfactorregulatingtranscriptionofabatteryofgenesencodingxenobioticmetabolizingenzymesLossoffunction(genedisruption)studiesinmicehaddemonstratedthatAHRisinvolvedintoxiceffectsofdioxinsbuthadnotyieldedunequivocalresultsconcerningthephysiologicfunctionofthereceptorTounravelthebiologicfunctionsofAHRAnderssonetal(2002)performedgainoffunctionstudiesAconstitutivelyactiveAHRexpressedintransgenicmicereducedthelifespanofthemiceandinducedtumorsintheglandularpartofthestomachdemonstratingtheoncogenicpotentialoftheAHRandimplicatingthereceptorinregulationofcellproliferationBytargeteddisruptionoftheAhrgeneinmiceWalisseretal(2005)demonstratedthatAhrsignalinginendothelial/hematopoieticcellsisnecessaryfordevelopmentalclosureoftheductusvenosuswhereasAhrsignalinginhepatocytesisnecessarytogenerateadaptiveandtoxicresponsestodioxinexposureTheyconcludedthatcellspecificreceptorsignalinggeneratesdistinctAHRdependentphysiologicoutcomesREFERENCES1AnderssonPMcGuireJRubioCGradinKWhitelawMLPetterssonSHanbergAPoellingerLAconstitutivelyactivedioxin/arylhydrocarbonreceptorinducesstomachtumorsProcNatAcadSci99999099952002PubMedID121072862EmaMMatsushitaNSogawaKAriyamaTInazawaJNemotoTOtaMOshimuraMFujiiKuriyamaYHumanarylhydrocarbonreceptorfunctionalexpressionandchromosomalassignmentto7p21JBiochem1168458511994PubMedID78837603LeBeauMMCarverLAEspinosaRIIISchmidtJVBradfieldCAChromosomallocalizationofthehumanAHRlocusencodingthestructuralgenefortheAhreceptorto7p21p15CytogenetCellGenet661721761994PubMedID81250164MatikainenTPerezGIJurisicovaAPruJKSchlezingerJJRyuHYLaineJSakaiTKorsmeyerSJCasperRFSherrDHTillyJLAromatichydrocarbonreceptordrivenBaxgeneexpressionisrequiredforprematureovarianfailurecausedbybiohazardousenvironmentalchemicalsNatureGenet283553602001PubMedID114553875MickaJMilatovichAMenonAGrabowskiGAPugaANebertDWHumanAhreceptor(AHR)genelocalizationto7p15andsuggestivecorrelationofpolymorphismwithCYP1A1inducibilityPharmacogenetics7951011997PubMedID91701466OhtakeFBabaATakadaIOkadaMIwasakiKMikiHTakahashiSKouzmenkoANoharaKChibaTFujiiKuriyamaYKatoSDioxinreceptorisaliganddependentE3ubiquitinligaseNature4465625662007PubMedID173927877OhtakeFTakeyamaKMatsumotoTKitagawaHYamamotoYNoharaKTohyamaCKrustAMimuraJChambonPYanagisawaJFujiiKuriyamaYKatoSModulationofoestrogenreceptorsignallingbyassociationwiththeactivateddioxinreceptorNature4235455502003PubMedID127741248ShimizuYNakatsuruYIchinoseMTakahashiYKumeHMimuraJFujiiKuriyamaYIshikawaTBenzo[a]pyrenecarcinogenicityislostinmicelackingthearylhydrocarbonreceptorProcNatAcadSci977797822000PubMedID106391569WalisserJAGloverEPandeKLissALBradfieldCAArylhydrocarbonreceptordependentliverdevelopmentandhepatotoxicityaremediatedbydifferentcelltypesProcNatAcadSci10217858178632005PubMedID16301529CONTRIBUTORSAdaHamoshupdated4/12/2007PatriciaAHartzupdated1/27/2006AdaHamoshupdated5/29/2003VictorAMcKusickupdated9/20/2002AdaHamoshupdated7/13/2001VictorAMcKusickupdated2/9/2000VictorAMcKusickupdated8/19/1997CREATIONDATEVictorAMcKusick12/20/1994EDITHISTORYalopez4/12/2007mgross2/2/2006terry1/27/2006mgross5/30/2003mgross5/30/2003terry5/29/2003cwells9/24/2002carol9/20/2002alopez10/29/2001alopez10/15/2001alopez7/16/2001terry7/13/2001carol1/17/2001mgross3/1/2000terry2/9/2000jenny8/22/1997terry8/19/1997carol1/17/1995carol12/21/1994terry12/20/1994Copyright©19662007JohnsHopkinsUniversityDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardDisclaimerWritetotheHelpDeskPrivacyPolicyNCBINLMNIH