Thedifferentiationofkeratinocytesconstantlyreplenishestheupperlayersofhumanskinweloseeachday.Onefactorthatcontributestoterminalkeratinocytedifferentiationisincreasedlevelsofintracellularcalcium.Addingcalciumtothemediumofculturedkeratinocyteselevatesintracellularcalciumandtriggersdifferentiation.IntracellularcalciumlevelsarealsoincreasedinresponsetophospholipaseCactivation,producingIP3andreleasingcalciumfromstoresintheER.Intracellularcalciumaltersmultiplesignalingpathways,oneofwhichisbindingtocalmodulintoactivatetheserine-threonineproteinphosphatasecalcineurin.CalcineurindephosphorylatesandactivatesthetranscriptionfactorNFATandbothcalcineurinandNFATareexpressedindifferentiatingkeratinocytes.ActivatedNFATcanregulatetranscriptionthroughbindingitsowncognateDNAbindingsite.OneMarkerofkeratinocytedifferentiation,thep21gene,isactivatedbyNFATbyadifferentmechanism,withNFATactivatingthep21promoterbyactingasacoactivatorforthetranscriptionfactorsSp1andSp3.AnotherproteinactivatedbycalciumthatmaybeinvolvedinkeratinocytedifferentiationisproteinkinaseC(PKC).OnesubstrateofactivatedPKCisMARCKS(myristoylatedalanine-richkinaseCsubstrate).PhosphorylationofMARCKSbyPKCinintactkeratinocytesisnotinducedduringcalcium-induceddifferentiation,butdoesincreasewhentestedinvitro.PKCactivityisincreasedbycalciumduringkeratinocytedifferentiationbutPKCMARCKSphosphorylationisblockedbytheformationofacomplexbetweencalmodulinandMARCKS.Theimmunosuppressantscyclosporin-A(CsA)andFK506inhibitTcellactivationthroughindirectinhibitionofNFATactivationandhaveseveralsideeffectsincludingchangesintheskin,suggestingthatcalcineurinactivitymayplayaroleinnormalskinphysiology.CsAisusedtotreatpsoriasis,adiseaseinvolvingabnormalproliferationofskincells.TheactivityofCsAintreatingpsoriasismayinvolveinhibitionofimmunecells,butmayalsodirectlyinvolveinhibitionofcalcineurinactivityinkeratinocytes.

Contributor:KosiGramatikoff,RogerAndersonPh..

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