ThemostrecognizedmechanismbywhichperoxisomeproliferatorsregulatedgeneexpresssionisthroughaPPAR/RXRheterodimericcomplexbindingtoaperoxisomeproliferator-responseelement(PPRE)(classicalmechanism).However,therearethepossibilityofseveralvariationsonthistheme:1).TheperoxisomeproliferatorinteractswithPPARthatpreexistsasaDNAcomplexwithassociatedcorepressorsproteins.Theinteractionwithligandcausesreleaseofthecorepressorandassociationwithacoactivator,resultingintheclassicalmechanism.2).TheperoxisomeproliferatorinteractswithPPARasasolublememberofthenucleus.ThebindingofligandresultsinRXRheterodimerization,DNAbindingandcoactivatorrecruitment.3).Inthisscenario,PPARexistsinthecytosol,perhapscomplexedtoheatshockprotein90and/orotherchaperones.Bindingofperoxisomeproliferatorcausesaconformationalchangeandtranslocationintothenucleus.Scenarios4and5requireregulationofgeneexpressionvianon-classicalmechanisms:4).PPARiscapableofinteractingwith,andformingDNAbindingheterodimerswith,severalnuclearreceptorsincludingthethyroidhormonereceptor.Thebindingsiteforthisnon-RXRheterodimerneednotbetheclassicDR-1motiffoundinthePPRE.5).PPARmayparticipateintheregulationofgeneexpressionwitoutbindingtoDNA.Byassociationwithtranscriptionfactorssuchasc-junorp65,PPARdiminishestheABIlityofAP1orNFBtobindtotheircognateDNAsequences,respectively.Alsoshowninthisschemearetwomeanstomodifytheperoxisomeproliferatorresponse.Mostimportantly,growthfactorsignalinghasapronouncedaffectonPPARviapost-translationalmodification.PPARisaphosphoproteinanditsactivityisaffectedbyinsulin.SeveralkinasepathwaysaffectsPPARa"sactivity,althoughthespecifickinasesandphosphorylationsiteshavenotbeenconclusivelydetermined.

Contributor:JackVandenHeuvel

REFERENCES:Escher,P.andWahli,W.Peroxisomeproliferator-activatedreceptors:insightintomultiplecellularfunctions.MutatRes,448:121-138,2000Gelman,L.,Fruchart,J.C.,andAuwerx,J.Andupdateonthemechanismsofactionoftheperxisomeproliferator-activatedreceptors(PPARs)andtheirrolesininflammationandcancer.CellMolLifeSci,55:932-943,1999Kersten,S.,Desvergne,B.,andWahli,W.RolesofPPARsinhealthanddisease.Nature,405:421-424,2000Peters,J.M,andVandenHeuvel,J.P.Peroxisomes,peroxisomeproliferatorsandperoxisiomeproliferator-activatedreceptors(PPARs).In:J.P.vandenHeuvel,G.H.Perdew,W.B.MattesandW.F.Greenlee(eds.),CellularandMolecularToxicology,Vol.14,pp.Peters,J.M,andVandenHeuvel,J.P.Peroxisomes,peroxisomVandenHeuvel,J.P.Peroxisomeproliferator-activatedreceptors(PPARS)andcarcinogenesis.ToxicolSci,47:1-8,1993

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