Modulation of Microphthalmia-associated Transcription Factor Gene Expression Alters Skin Pigmentation

• Published in: Journal of investigative dermatology Vol. 119; no. 6; pp. 1330 - 1340
• Main Authors: Lin, C.B., Babiarz, L., Liebel, F., Kizoulis, M., Gendimenico, G.J., Seiberg, M., Roydon Price, E., Fisher, D.E.
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01.12.2002; Nature Publishing; Elsevier Limited
• Subjects: 8,11,14-Eicosatrienoic Acid - pharmacology; Animals; Antioxidants - pharmacology; Biological and medical sciences; Cells, Cultured; Colforsin - pharmacology; DNA-Binding Proteins - genetics; Drugs, Chinese Herbal - pharmacology; Gene Expression - drug effects; Gene Expression - radiation effects; Humans; lipoic acid; Luciferases - genetics; Malformations of the eye; Medical sciences; Melanocytes - physiology; microphthalmia; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase - metabolism; Ophthalmology; pigmentation; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - radiation effects; Skin Pigmentation - drug effects; Skin Pigmentation - physiology; Skin Pigmentation - radiation effects; Stilbenes - pharmacology; Swine; Thioctic Acid - pharmacology; traditional Chinese medicine; Transcription Factors - genetics; tyrosinase; ultraviolet; Ultraviolet Rays; pigmentation; traditional Chinese medicine; lipoic acid; microphthalmia; tyrosinase; ultraviolet; Human; Lipoic acid; Cell culture; Ultraviolet radiation; lipoic acid/microphthalmia/pigmentation/traditional Chinese medicine/tyrosinase/ultraviolet B; Melanocyte; Skin; Melanogenesis; Gene expression; Transcription factor; Pigmentation; Microphthalmia
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1046/j.1523-1747.2002.19615.x

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.