BackgroundInformation | CREB,cyclicAMP(cAMP)responseelement-bindingprotein,isaubiquitouslyexpressedbasicleucinezippertranscriptionfactorthatfunctionsinglucosehomeostasisandstimulatestheexpressionofnumerousgenesinresponsetogrowthfactors,hormones,neurotransmitters,ionfluxes,stresssignals,andhasbeenimplicatedinmemorybecauseifitsapparentroleinsynapticplasticity.CREBfunctionseitherbyitselforwithrelatedfamilymembers,whichincludeCREB,CREM,andATF-1,byforminghomo-andheterodimersthroughtheirbasicleucinezipper(bZIP)domains.TheCREBsignalingpathwayisactivatedbyextracellularligandsthatbindtocellsurfacereceptorsandrelaytheirmessagethroughvariousintracellularsecondmessengersresultingultimatelyintheactivationofnuclearCREBthroughphosphorylationofthetransactivationdomainatserine1332,4.TheclassicalmodelofCREBactivationisthroughPKA(cAMP-dependentproteinkinase).Inthenon-activestate,PKAresidesinthecytoplasmasaninactiveheterotetramerofpairedregulatoryandcatalyticsubunits.StimulationofcAMPcausesthereleasesofthecatalyticsubunitsofPKAthatpassivelydiffuseintothenucleusandinitiatesgeneexpressionbyphosphorylatingCREBatitstransactivationdomainonserine1331,2,3,4.CREBmediatestheactivationofcAMP-responsivegenesbybindingasadimertoaconservedcAMP-responsiveelement(CRE),5’-TGACGTCA-3’,locatedwithinthepromoterregionoftargetgenes.Targetgeneactivationisterminatedbytheserine/threoninephosphatasesPP-1-mediateddephospho-rylationofCREB.
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