the regulation of skin pigmentation

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    TheRegulationofSkinPigmentation

    MelanogenesisoccursinmelanosomesMelaninconsistsofdistinctforms:-Eumelanin:brown/black-Pheomelanin:yellow/redratioimp

    Constitutivepigmentation:-Geneticallydetermined/absofexternalinfluencesFacultativepigmentation:

    - pigmentationduetoaphysiologicalfactor

    Regulationofconstitutivepigmentation/MC-1R

    Regulationoffacultativepigmentation/UVR

    Whatdeterminesphenoype?Oxy/deoxyhaemoglobinCarotenoids

    MelaninWhatcontrolsPigmentation?

    >125distinctgenes

    -developmentofmelanoblasts-differentiation&survivalmelanocytes

    >25genes-biogenesis&functionofmelanosomes/proteinsMelanosomes,whicharecloselyrelatedtolysosomesandarewithinthefamilyoflysosome-relatedorganelles(LROs),requireanumberofspecificenzymaticandstructuralproteinstomatureandbecome

    competenttoproducemelaninCriticalenzymesinclude:

    1. Tyrosinase2. TYRP-1(tyrosinaserelatedprotein-1)3. DCT(DOPAchrometautomerase)

    Criticalstructuralproteins:1-Pmel172-MART1forstructuralmaturationmelanosomes

    Mutations:enzymes&structuralproteins:-inheritedpigmentarydisordersegAlbinism:Tyrosinasedysfunction

    MelanocytesSpecialise:inthesynthesisofmelaninDerived:melanoblastsVisiblephenotype:Accuratemigration,distribution&functioningMblasts/McyteLocation:-basallayerepidermis-connectedtokeratinocytes,fibroblasts

    -hairfollicle:bulb/ORSsebaceousgland-eye,innerear

    Melanogenesiswhere?melanosomes

    3distinctmelanins:- Eumelanin:darkandblackhair

    o DHImelanin-darkbrown/blackinsolublemelanino DHICA-melanin-lighterbrowncolor,moderatelysolubleandofintermediatesize

    Pheomelanin:Red/freckledhair--yellow-redsolublemelanin

    melanosomesmature:-Transferredcitesynthesis=perikaryondendrites-neighbouringkeratinocytes

    Melanocytestructure

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    whydodifferencesinhumanskincolourexist?- Tyrosinaseactivity-- No.&sizeofMsomes- TransferofmatureMsomesKcytes- MC:KC1:10- MCcontributemelaninto40KC-

    Caucasianskin/melanosomes:

    -smaller/lessmelanin-severalMsomesaretransferredKcytes

    -Msomesdegradedinlowerepidermallayers

    Blackskin/melanosomes:-Larger/moremelanin

    -MsomestransferredindividuallyKcytes

    -MsomesdegradedinupperepidermallayersConstitutiveandFacultativePigmentation

    Constitutive:-Geneticallydetermined-Absenceofexternal

    influences

    Facultative:-pigmentationinresponsestimulation

    -UVRmajorregulatorConstitutivePigmentation

    DevelopmentalConsiderations(EMI)refertoproximateparacrineorjuxtacrinecross-talkbetweenstromalfibroblastsandtissueepithelia(EMT),whichrefertothetransdifferentiationofepithelialcellstoafibroblast-likephenotype.EMIaswellasEMTisrequiredforthedevelopmentofvariousorgans;thekeysignalingpathways

    involvedinEMIincludehomeobox(HOX),fibroblastgrowthfactors,sonichedgehogs,Wnt/B-catenin/Lef1,andbonemorphogenesisproteins.

    Determinationfactors

    Migrationofmelanoblasts Survival&differentiationmelanocytes Expressionenzymatic/structuralconstituentsMsomes Synthesisofeuandpheomelanin TransportofMsomesdendrites TransferMsomeskeratinocytes Distributionofmelanininsuprabasallayersoftheskin

    Melanocortin-1Receptor-GPCRMajorctrlpointinregulatinghumanpigmentationRegulatesquantity&qualityofmelanins

    AgonistsMC-1R

    -MSH&ACTH(precursorpeptidePOMC)Synthesised:Skincells/Mcytes&KcytesActivationMC-1R

    - stimulatesexpressionofmelanogeniccascade-synthesisofeumelanin-MSH&ACTH

    Mcytedendricity&proliferationexpressionofMC-1Rgene

    MelanogenesisDendricityproliferation

    AntagonistMC-1R

    Agoutisignallingprotein(ASP)-stimulatessynthesisofpheomelanin

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    MC-1Rpolymorphisms

    RedhairandfairskinAllelicvariants/associatedwithredhair/fairskin-Arg151Cys,Arg160Trp,Asp294His

    LossoffunctionMC-1R:-affects-MSH/ACTHbinding-subsequentsignallingHighlyassociatedwith:-poortanning

    -riskofmelanoma

    FacultativePigmentation

    Regulatedby:UVAradiation/tanningreaction

    Immediatetanning

    -Occurswithinminsofexposure&persistsforhrspersistentskindarkening

    -Lastsseveraldays

    -oxidationandpolymerisationofexistingmelanin-redistributionofexistingmelanosomes

    Delayedtanning

    -OccursseveraldaysafterUVRexposure-Activationofmelanocytefunction-Mcyteproliferation&dendricity

    -MITFexpression&

    -downstreammelanogenicproteins:Pmel17 MART-1 Tyrosinase TRP-1 DCT increasedMelanogenesis

    -Increased levels of PAR2 in keratinocytes which increases uptake and distribution of melanosomes

    EMandEKrespondtoUVexposure:

    - synthesisandsecretionof-MSH&ACTHexpressionandfunctionofMC-1REnhancesMcyteresponsesto-MSH&ACTH

    MK

    ET-1MC1R+EDNRB(EM) IL-1ACTH, MSH, endothelin 1, and bFGF SCF(stemcellfactor) NGF(nervegrowthfactor)preventsmelanocyteapoptoticcelldeathfollowingUVexposure Stimulationofp53increasesexpressionofthePOMCgene,leadingtoincreasedsecretionof

    MSHandstimulationofMC1Rfunctioninneighboringmelanocytes

    Fibroblastsgrowth factors -HGF, bFGF, and SCF, all factors that stimulate pigmentation via their

    receptors on melanocytes

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    Regulation of human skin pigmentation and responses to ultraviolet radiation

    Pigmentationofhumanskiniscloselyinvolvedinprotectionagainstenvironmentalstresses,inpartic-ularexposuretoultraviolet(UV)radiation.Itiswellknownthatdarkerskinissignificantlymoreresist-

    anttothedamagingeffectsofUV,suchasphoto-carcinogenesisandphotoaging,thanislighterskin.Constitutiveskinpigmentationdependsontheamountofmelaninanditsdistributioninthattis-sue.

    MelaninissignificantlyphotoprotectiveandepidermalcellsindarkerskinincurlessDNAdam-agethandothoseinlighterskin.ThisreviewsummarizescurrentunderstandingoftheregulationofconstitutivehumanskinpigmentationandresponsestoUVradiation,withemphasisonphysiologicalfactorsthatinfluencethoseprocesses.Furtherresearchisneededtocharacterizetheroleofskinpigmentationtoreducephotocarcinogenesisandtodevelopeffectivestrategiestominimizesuchrisks.-Melanocytedensityisalmostidenticalinskinofdifferentcolorsandracialorigins-Constitutiveskinpigmentationdependsprimarilyontheamountofmelaninpresentandonitsdistribution.-Melaninmostcertainlyisphotoprotectivetoasignificantdegree

    darkerskinincursignificantlylessDNAdamagethaninlighterskin.Interestingly,melanogenicactivitiesincreasemoreefficientlyindarkerskinthaninlighterskinexposedtocomparabledosesofUV.melanogenicproteins

    - thetranscriptionfactorMITFrespondsmostquicklytoUV(within12days).- tyrosinase,Tyrp1,Pmel17,andDCTisslower(c.1week)- increasesinmelaninsynthesistakeabitlonger(c.3weeks)- increasesinmelano-cytedensitytakeeenlonger(45weeks).

    Thedistributionofmelaninintheskinplaysanimportantroleinvisiblepigmentationandnodoubtinphoto-protectivecapacity.Although,thereisaninitialsurge(1week)intheupwardmigrationofexistingpigmenttowardsthesurfaceoftheepidermis,thebalanceinpigmentdistributionisrestoredby45weekswhennewsynthesisofmelaninhasbeenestablished.Itisclearthatrelativelysmallchangesin

    melanincontentand/ordistributioncanmakerelativelylargechangesinvisiblepigmentation.Thoseaffectnotonlyconstitutivepigmentationthatdefinesracial/ethnicdifferencesbutalsoresponsestoUVexposure.

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