View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector COMMENTARY in mammalian gene regulation, it is high- See related article on pg 784 ly likely that SNPs that alter the regula- tion of gene expression may function at some distance from the target gene. This NADPH:Quinone Oxidoreductase-1 concept is exemplified in the context of melanocyte biology by recent associa- as a New Regulatory Enzyme That tion studies into pigmentation regulation in the eye. The presence of a single SNP Increases Melanin Synthesis located within intron 86 of the HERC2 Yuji Yamaguchi1, Vincent J. Hearing2, Akira Maeda1 gene was found to be the major determi- 1 nant of blue/brown eye-color phenotypes and Akimichi Morita in humans (Sturm et al., 2008). Although Most hypopigmenting reagents target the inhibition of tyrosinase, the key this finding may have provided impe- enzyme involved in melanin synthesis. In this issue, Choi et al. report that tus to investigate the role of this gene in NADPH:quinone oxidoreductase-1 (NQO1) increases melanin synthesis, melanocyte function, prior knowledge probably via the suppression of tyrosinase degradation. Because NQO1 of melanocyte biology suggests that this was identified by comparing normally pigmented melanocytes with SNP is likely to regulate the expression hypopigmented acral lentiginous melanoma cells, these results suggest of the neighboring OCA2 gene, with its various hypotheses regarding the carcinogenic origin of the latter. role already firmly established in the pro- Journal of Investigative Dermatology (2010) 130, 645–647. doi:10.1038/jid.2009.378 cess of pigmentation. To fully appreciate and extend these findings, the genetic associations and locus interactions of these candidate sus- Enzymes that regulate skin pigmentation plays the critical role in melanin syn- ceptibility genes must also be examined Melanin synthesis by melanocytes is one thesis, and various factors, including in the wider context of the autoimmune of the most important parameters regu- the copper-transporter ATP7A, have diseases that accompany vitiligo. lating skin pigmentation (Yamaguchi et the capacity to modulate its enzymat- al., 2007a), and more than 150 pigment ic activity (Setty et al., 2008). Indeed, CONFLICT OF INTEREST The authors state no conflict of interest. genes have now been identified. The most hypopigmenting reagents are cosmetic industry has developed numer- intended to suppress tyrosinase activ- REFERENCES ous hypopigmenting (depigmenting or ity. Additionally, two variants of oculo- Boissy RE, Spritz RA (2009) Frontiers and whitening) reagents to suppress melanin cutaneous albinism in humans (OCA1A controversies in the pathobiology of vitiligo: synthesis in order to meet the needs of and OCA1B) are caused by mutations in separating the wheat from the chaff. Exp Dermatol 18:583–5 customers with hyperpigmenting condi- tyrosinase. Tyrosinase is the rate-limiting tions such as chloasma (melasma) and/ enzyme that mediates hydroxylation Jin Y, Mailloux CM, Gowan K et al. (2007) NALP1 in vitiligo-associated multiple autoimmune or ephelides (freckles) (Solano et al., of tyrosine to dopaqui none and the disease. N Engl J Med 356:1216–25 2006). There is also a demand for hyper- oxidation of 5,6-dihydroxyindole (DHI) Jin Y, Riccardi SL, Gowan K et al. (2010) Fine- pigmenting (artificial tanning) reagents to indole-5,6-quinone, which pro- mapping of vitiligo susceptibility loci on to treat vitiligo and other hypopigment- duces eumelanin (Figure 1). DCT is a chromosomes 7 and 9 and interactions with NLRP1 (NALP1). J Invest Dermatol 130:774–83 ing diseases, and there are societies in tautomerase that converts dopachrome which tanning is perceived as beautiful to DHI-2-carboxylic acid (DHICA), Liu L, Li C, Gao J et al. (2009) Genetic polymorphisms of glutathione S-transferase and and healthy. Taking together these obser- whereas TYRP1 is a DHICA oxidase that risk of vitiligo in the Chinese population. J Invest vations, methods of controlling melanin further stimulates eumelanin synthesis. Dermatol 129:2646–52 synthesis have considerable significance Consequently, melanogenic enzymes Spritz RA, Gowan K, Bennett DC et al. for patients with pigmentary disorders that act within melanosomes are critical (2004) Novel vitiligo susceptibility loci and in the general marketplace. for the production of the pigmented bio- on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, Enzymes involved in melanin synthe- polymer melanin. and their roles in an autoimmune diathesis. sis include tyrosinase, tyrosinase-related Am J Hum Genet 74:188–91 protein-1 (TYRP1), and dopachrome NQO1 as an enhancer Sturm RA, Duffy DL, Zhao ZZ et al. (2008) A single tautomerase (DCT) (Yamaguchi and of tyrosinase activity SNP in an evolutionary conserved region Hearing, 2009). Among these enzymes Yoon’s group has identified NADPH: within intron 86 of the HERC2 gene determines human blue-brown eye color. Am J Hum Genet in the tyrosinase family, tyrosinase quinone oxidoreductase-1 (NQO1) 82:424–31 Taieb A, Picardo M (2009) Clinical practice. Vitiligo. N Engl J Med 360:160–9 1Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of 2 Waterman EA, Gawkrodger DJ, Watson PF et al. Medical Sciences, Nagoya, Japan and Laboratory of Cell Biology, National Cancer Institute, (2009) Autoantigens in vitiligo identified by National Institutes of Health, Bethesda, Maryland, USA the serological selection of a phage-displayed Correspondence: Yuji Yamaguchi, Department of Geriatric and Environmental Dermatology, Nagoya melanocyte cDNA expression library. J Invest City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya Dermatol 130:230–40 467-8601, Japan. E-mail: [email protected] www.jidonline.org 645 COMMENTARY (Dinkova-Kostova et al., 2002). Keap1 Clinical Implications binds to Nrf2, which translocates to • NQO1 is a newly identified regulatory enzyme that increases tyrosinase the nucleus in response to carcinogens activity, probably by suppressing its degradation. and oxidants, followed by activation • Identification of a novel regulatory enzyme provides new of the antioxidant response element pharmacologic opportunities to treat pigmentary disorders. of the NQO1 gene. It seems likely that upregulated NQO1 enhances the • Likewise, identification of a novel enzyme may provide leads for the expression of tyrosinase independent- pharmacologic treatment of melanoma. ly of its regulation by MITF, because NQO1 does not affect the expression of tyrosinase at the mRNA level or the expression of MITF at either the by comparing hypopigmented acral mRNA level in tissue culture. Choi mRNA or the protein levels. Choi et lentiginous melanoma cells with et al. conclude that NQO1 positively al. hypothesize that NQO1 suppresses their normal counterparts, pigmented regulates melanin synthesis, probably the ubiquitin–proteasome system that melanocytes obtained from the back by stabilizing tyrosinase protein. would normally degrade tyrosinase. skin of the same patient (Choi et al., These findings triggered the Other factors that affect tyrosinase this issue). NQO1 is an enzyme that authors’ interest in elucidating the trafficking in melanocytes may be catalyzes the two-electron reduction mechanism(s) by which NQO1 involved in the selective upregulation and the detoxification of quinones upregulates tyrosinase activity. of tyrosinase in response to NQO1. (including coenzyme Q10, also known Keap1 (Kelch-like ECH-associated as ubiquinone, and p-benzoquinone) protein 1) regulates the expression NQO1 as a therapeutic target to broad-sense hydroquinones of NQO1 via Nrf2, a member of the for acral melanoma (including ubiquinol and narrowly NF-E2 family of nuclear basic leucine To identify NQO1 as an enzyme that defined hydroquinone, also known as zipper transcription factors (Figure 2) increases melanin synthesis, Choi 1,4-benzenediol). The lower section of Figure 1 shows a representative reac- tion for NQO1, which may play a role Eumelanin in melanin synthesis, specifically the conversion of dopaquinone to dopa- Tyrosinase TYRP1 chrome via leuko dopachrome. NQO1, CO H HO HO one of the phase 2 enzymes, ordinar- 2 NH 2 HO HO CO H ily protects cells against free radical HO N N 2 damage and oxidative stress. Because H H Tyrosine hydro quinone is a well-known hypop- DHI DHICA CO igmenting reagent, NQO1 may nega- Tyrosinase 2 DCT tively regulate skin pigmentation via an HO increased production of hydroquinone O CO2H O NH2 within melanocytes. Indeed, the authors HO CO H CO2H O N 2 HO N demonstrate that overexpression of H NQO1 results in a modest decrease in Dopaquinone Leukodopachrome Dopachrome TYRP1 and microphthalmia-associated Cysteine transcription factor (MITF, the mas- ter regulator of skin pigmentation) at NADPH NADP+ Pheomelanin protein levels (Figure 2). O OH On the other hand, melanogenesis increased in concert with increasing NQO1 levels of NQO1 in the various mela- O OH noma cell lines tested. Additionally, p-Benzoquinone Hydroquinone the inhibition of NQO1 resulted in a decrease in MITF, tyrosinase, and Figure 1. Key players in melanin biosynthesis and NQO1 as an oxidoreductase that mediates TYRP1 (but not DCT) at protein lev- the conversion of quinones to hydroquinones. Tyrosinase, DCT, and TYRP1 are enzymes that els in tissue culture and in a reduc- convert tyrosine (and DHI) to dopaquinone (and eumelanin),