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Angiopoietin-Like 4 Regulates Epidermal Differentiation 英文参考文献
Angiopoietin-Like4RegulatesEpidermalDifferentiation
MintuPal1.,MingJieTan1.,Royston-LukeHuang1,YanYihGoh1,XiaoLingWang1,MarkBoonYang
Tang2,NguanSoonTan1*
1SchoolofBiologicalSciences,CollegeofScience,NanyangTechnologicalUniversity,Singapore,Singapore,2NationalSkinCentre,Singapore,Singapore
Abstract
The nuclear hormone receptor PPARb/d is integral to efficient wound re-epithelialization and implicated in epidermal
maturation. However, the mechanism underlying the latter process of epidermal differentiation remains unclear. We
showed that ligand-activated PPARb/d indirectly stimulated keratinocyte differentiation, requiring de novo gene
transcriptionandproteintranslation.Usingorganotypic skincultures constructedfromPPARb/d-andangiopoietin-like4
(ANGPTL4)-knockdown human keratinocytes, we showed that the expression of ANGPTL4, a PPARb/d target gene, is
essentialforthereceptormediatedepidermaldifferentiation.Thepro-differentiationeffectofPPARb/dagonistGW501516
wasalsoabolishedwhenkeratinocyteswereco-treatedwithPPARb/dantagonistGSK0660andsimilarlyinorganotypicskin
cultureincubatedwithblockingANGPTL4monoclonalantibodytargetedagainsttheC-terminalfibrinogen-likedomain.Our
focusedreal-timePCRgeneexpressionanalysiscomparingtheskinbiopsiesfromwildtypeandANGPTL4-knockoutmice
confirmedaconsistentdown-regulationofnumerousgenesinvolvedinepidermaldifferentiationandproliferationinthe
ANGPTL4-knockoutskin.WefurthershowedthatthedeficiencyofANGPTL4inhumankeratinocytesandmiceskinhave
diminished expressionof various proteinkinaseC isotypes andphosphorylated transcriptional factor activatorprotein-1,
which are well-established for their roles in keratinocyte differentiation. Chromatin immunoprecipitation confirmed that
ANGPTL4 stimulated the activation and binding of JUNB and c-JUN to the promoter region of human involucrin and
transglutaminasetype1genes,respectively.Takentogether,weshowedthatPPARb/dregulatesepidermalmaturationvia
ANGPTL4-mediatedsignallingpathway.
Citation:PalM,Ta
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