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81928419.Pdf View metadata, citation and similar papers at core.ac.uk brought to you by CORE providedORIGINAL by Elsevier - ARTICLE Publisher Connector See related Commentary on pages 1215 and 1218 Modulation of Microphthalmia-associated Transcription Factor Gene Expression Alters Skin Pigmentation C. B. Lin,L. Babiarz,F. Liebel,E. Roydon Price, n M. Kizoulis,G. J. Gendimenico,D. E. Fisher, n and M. Seiberg Johnson & Johnson Skin Research Center,CPWW,Skillman,NJ 08558,U.S.A.; nDepartment of Pediatric Hematology/Oncology,Dana Farber Cancer Research Institute and Harvard Medical School,Boston,MA 02115,U.S.A. The microphthalmia-associated transcription factor is reduced microphthalmia-associated transcription factor implicated in melanocyte development and in the reg- and tyrosinase promoter activities. These agents also in- ulation of melanogenesis. Microphthalmia-associated hibited the forskolin- and ultraviolet B-stimulated pro- transcription factor is thought to bind to the M-box moter activities of these genes and signi¢cantly reduced promoter elements of tyrosinase, tyrosinase-related tyrosinase activity in melanocyte cultures, resulting in protein-1 and dopachrome tautomerase/tyrosinase- depigmentation. Overexpressed microphthalmia-asso- related protein-2 and transactivate these genes, resulting ciated transcription factor was capable of rescuing the in increased pigmentation. Using a luciferase reporter repressive e¡ects of these compounds on the cotrans- construct driven by the microphthalmia-associated fected tyrosinase promoter. Dark-skinned Yucatan transcription factor promoter, we identi¢ed agents that swine treated with these agents showed visible skin modulate microphthalmia-associated transcription fac- lightening, which was con¢rmed histologically, whereas tor promoter activity. Changes in endogenous micro- ultraviolet B-induced tanning of light-skinned swine phthalmia-associated transcription factor expression was inhibited using these agents. Our ¢ndings suggest levels upon treatment with these agents were con¢rmed that modulation of microphthalmia-associated tran- using northern and western blots, and their pigmentary scription factor expression can alter skin pigmentation modulating activities were demonstrated. Ultraviolet B and further con¢rm the central role of microphthal- irradiation and traditional Chinese medicine-1, a natur- mia-associated transcription factor in melanogenesis. al extract used in traditional Chinese medicine, upregu- Key words: lipoic acid/microphthalmia/pigmentation/traditional lated microphthalmia-associated transcription factor Chinese medicine/tyrosinase/ultraviolet B. J Invest Dermatol gene expression and enhanced tyrosinase activity 119:1330^1340,2002 in vitro. Dihydrolipoic acid, lipoic acid, and resveratrol kin pigmentation,resulting from the production and and dopachrome tautomerase (DCT,also known as tyrosinase re- distribution of melanin in the epidermis,is the major lated protein-2,TRP-2) are involved in the enzymatic conversion physiologic defense against solar irradiation. In mam- of tyrosine to melanin (Korner and Pawelek,1982; Barber et al, mals,melanogenesis is stimulated by ultraviolet (UV)B 1984; Hearing and Jimenez,1987; Prota,1988; Jimenez-Cervantes irradiation, a-melanocyte-stimulating hormone (a-MSH), et al,1994; Yokoyama et al,1994). The promoter sequences of tyr- Sand cyclic adenosine monophosphate (cAMP)-elevating agents osinase,Tyrp1,and DCT share a highly conserved motif termed (e.g.,forskolin,isobutylmethylxanthine) (Abdel-Malek et al, the M-box,which contributes to their melanocyte-speci¢c 1987). Melanin is synthesized in epidermal melanocytes, expression (Yasumoto et al,1997; Aksan and Goding,1998). The and then transferred into epidermal keratinocytes via the melano- microphthalmia-associated transcription factor (MITF),a basic cytes’dendrites (Le Douarin,1982). Three melanocyte-speci¢c en- helix^loop^helix leucine zipper transcription factor,is thought zymes,tyrosinase,tyrosinase-related proteins-1 (TRP-1/Tyrp1) to bind to the M-box and transactivates the tyrosinase,Tyrp1, and DCT promoters (Hemesath et al,1994; Yasumoto et al,1997; Aksan and Goding,1998). MITF is involved in melanocyte devel- Manuscript received March 7,2002; revised June 24,2002; accepted for opment and survival (Moore,1995; Fisher,2000),and overexpres- publication August 17,2002 sion of MITF in NIH/3T3 ¢broblasts could induce dendricity Reprint requests to: Dr Miri Seiberg,Johnson & Johnson Skin Research and tyrosinase and Tyrp1 expression (Tachibana et al,1996). Center,Consumer and Personal Care Group,199 Grandview Road,Skill- Homozygous mutations at the mouse microphthalmia (Mi) locus man,NJ 08588,U.S.A. Email: [email protected] lead to a complete loss of pigmentation due to melanocyte loss Abbreviations: MITF,microphthalmia-associated transcription factor; (Silvers,1979; Tachibana et al,1994). Mutations in the human Tryp-1,tyrosinase-related protein-1; LA,lipoic acid; DHLA,dihydrolipoic acid; TCM-1,traditional Chinese medicine-1; CRE,cAMP response homolog of the mouse Mi gene result in abnormal pigmentation element; MSH,melanocyte-stimulating hormone; DOPA,3,4-dihydroxy- and deafness,as observed in Waardenburg syndrome type IIA phenylalanine; F&M,Fontana^Mason; NHEM,normal human epidermal (Tachibana et al,1994; Tassabehji et al,1994,1995; Nobuku ni et al, melanocytes. 1996; Bondurand et al,2000). The MITF gene contains multiple 0022-202X/02/$15.00 Copyright r 2002 by The Society for Investigative Dermatology,Inc. 1330 VOL. 119,NO. 6 DECEMBER 2002 MODULATION OF MITF GENE EXPRESSION ALTERS SKIN PIGMENTATION 1331 0 4 promoters,which give rise to unique 5 exons,subsequently In brief,B16 cells (7 Â10 ) were lyzed in 0.1 M of HCl to inhibit spliced on to a common downstream coding region (Udono phosphodiesterase activity. Supernatants were collected,neutralized,and et al,2000). One of these alternative promoters is melanocyte spe- diluted. Following neutralization and dilution,a ¢xed amount of cAMP ci¢c (Fuse et al,1996) and contains a cAMP response element conjugate (alkaline phosphatase-labeled cAMP) was added to compete with cAMP present in the cell lysates for sites on a rabbit polyclonal (CRE) consensus motif. The melanocyte-speci¢c MITF promo- antibody immobilized on a 96 well plate. After a wash to remove excess ter CRE is believed to mediate cAMP-induced melanogenesis in conjugated and unbound cell lysate cAMP,a substrate solution was added response to MSH stimulation (Wong and Pawelek,1975; Halaban to the wells to determine the bound enzyme activity. The color et al,1984; Gordon et al,1989; Takahashi and Parsons,1990; Hunt development was stopped and the absorbance was read at 405 nm. et al,1994; Fuse et al,1996; Bertolotto et al,1998; Price et al,1998b). The intensity of the color was inversely proportional to the concentration The signi¢cance of MITF as a master regulator of melanogen- of cAMP in the cell lysates. All studies were repeated at least three times. esis led us to search for agents that modulate MITF expression, RNA isolation and northern blot analysis Total RNA was isolated and therefore might a¡ect skin pigmentation. Here we show TM that UVB irradiation and the natural extract traditional Chinese using RNA STAT-60 (TEL-TEST,Inc.,Friendswood,TX) according to manufacturer’s instructions. Twenty micrograms of total RNA were medicine-1 (TCM-1) activate the melanocyte-speci¢c MITF pro- separated on a 1% agarose gel,and transferred on to Gene Screen plus moter,whereas dihydrolipoic acid (DHLA),lipoic acid (LA), 0 membrane (Du Pont-NEN,Boston,MA). Hybridization was performed and resveratrol (trans-3,4,5-trihydroxystibene) reduce MITF in ExpressHybTM Hybridization Solution (Clontech,Palo Alto,CA) expression,and induce skin lightening in vivo. according to the manufacturer’s instructions,using a human MITF cDNA fragment (base pairs 58^1432) as a probe. Protein extraction and western blot analysis Western blot analysis MATERIALS AND METHODS was performed on B16 cell extracts as previously described (Sharlow et al, 2000). Brie£y,B16 cells were lyzed in RIPA bu¡er containing 1% nonidet- Reagents Chemicals were from Sigma (St Louis,MO). Pycnogenol was P40,0.5% sodium deoxycholate,0.1% sodium dodecyl sulfate, from Cogniz Corporation (Cincinnati,OH) and a concentrated green tea CompleteTM protease inhibitors (Boehringer Mannheim,Indianapolis, polyphenols extract was from Lipton (Grand Rapids,MN). TCM-1,an IN) and phosphatase inhibitors (1 mM sodium vanadate and 20 mM aqueous extract of the plant Astragulus membraneus Bunge. Ex Maxim was sodium £uoride) in PBS. RIPA lysates (20 mg per lane) were kindly provided by Dr Zhi Sheng He (Shanghai Institute of Material electrophoresed in 10% sodium dodecyl sulfate^polyacrylamide gel Medica,Chinese Academy of Science,Shanghai,China). electrophoresis gels and proteins were analyzed by enhanced chemi- luminescence western blotting (Amersham,Arlington Heights,IL). Cell cultures Dulbecco’s modi¢ed Eagle’s medium,fetal bovine serum, Antibodies used are monoclonal antibodies against Mi (Hemesath et al, trypsin,penici llin,and streptomycin were from Life Technologies 1998),and polyclonal antibody against tyrosinase ( aPEP-7 kind gift of Dr (Rockville,MD). Primary normal human epidermal melanocytes V.Hearing,National Cancer Institute,NIH,Bethesda,MD) and against a- (neonatal,NHEM) were purchased from Cascade Biologics,Inc. tubulin (loading control). (Portland,OR) and were maintained according to the manufacturer’s instructions. Human HaCaT keratinocytes
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