title: Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation.
abstract: The microphthalmia-associated transcription factor is implicated in melanocyte development and in the regulation of melanogenesis. Microphthalmia-associated transcription factor is thought to bind to the M-box promoter elements of tyrosinase, tyrosinase-related protein-1 and dopachrome tautomerase/tyrosinase-related protein-2 and transactivate these genes, resulting in increased pigmentation. Using a luciferase reporter construct driven by the microphthalmia-associated transcription factor promoter, we identified agents that modulate microphthalmia-associated transcription factor promoter activity. Changes in endogenous microphthalmia-associated transcription factor expression levels upon treatment with these agents were confirmed using northern and western blots, and their pigmentary modulating activities were demonstrated. Ultraviolet B irradiation and traditional Chinese medicine-1, a natural extract used in traditional Chinese medicine, upregulated microphthalmia-associated transcription factor gene expression and enhanced tyrosinase activity in vitro. Dihydrolipoic acid, lipoic acid, and resveratrol reduced microphthalmia-associated transcription factor and tyrosinase promoter activities. These agents also inhibited the forskolin- and ultraviolet B-stimulated promoter activities of these genes and significantly reduced tyrosinase activity in melanocyte cultures, resulting in depigmentation. Overexpressed microphthalmia-associated transcription factor was capable of rescuing the repressive effects of these compounds on the cotransfected tyrosinase promoter. Dark-skinned Yucatan swine treated with these agents showed visible skin lightening, which was confirmed histologically, whereas ultraviolet B-induced tanning of light-skinned swine was inhibited using these agents. Our findings suggest that modulation of microphthalmia-associated transcription factor expression can alter skin pigmentation and further confirm the central role of microphthalmia-associated transcription factor in melanogenesis.
authors.affiliation: Johnson & Johnson Skin Research Center, CPWW, Skillman, NJ 08558, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Lin
authors.forename: L
authors.initials: L
authors.lastname: Babiarz
authors.forename: F
authors.initials: F
authors.lastname: Liebel
authors.forename: E
authors.initials: E
authors.lastname: Roydon Price
authors.forename: M
authors.initials: M
authors.lastname: Kizoulis
authors.forename: G J
authors.initials: GJ
authors.lastname: Gendimenico
authors.forename: D E
authors.initials: DE
authors.lastname: Fisher
authors.forename: M
authors.initials: M
authors.lastname: Seiberg
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008544:Melanocytes / Q000502:physiology; D051739:Microphthalmia-Associated Transcription Factor; D014442:Monophenol Monooxygenase / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000528:radiation effects; D000077185:Resveratrol; D012880:Skin Pigmentation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013267:Stilbenes / Q000494:pharmacology; D013552:Swine; D008063:Thioctic Acid / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D014466:Ultraviolet Rays
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D004365:Drugs, Chinese Herbal; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D013267:Stilbenes; D014157:Transcription Factors; D005576:Colforsin; D008063:Thioctic Acid; D008156:Luciferases; D014442:Monophenol Monooxygenase; D015126:8,11,14-Eicosatrienoic Acid; D000077185:Resveratrol