Pigment cell research

Pigment Cell ResearchVolume 20, Issue 5 p. 334-335 Free Access Regulating melanosome transfer: who's driving the bus? Vincent J. Hearing, Vincent J. Hearing Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAE-mail: hearingv@nih.govSearch for more papers by this author Vincent J. Hearing, Vincent J. Hearing Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAE-mail: hearingv@nih.govSearch for more papers by this author First published: 10 August 2007 https://doi.org/10.1111/j.1600-0749.2007.00402.xCitations: 8AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Pigmentation of the skin has important consequences with respect to survival, not the least of which in humans is photoprotection from ultraviolet (UV) radiation. Thus in addition to serving as the major determinant dividing us into various racial and ethnic groups, skin pigmentation protects us from photocarcinogenesis and according to statistics of the National Cancer Institute for 2006, those in the United States with less pigmented skin are ∼70 times more likely to develop squamous or basal cell carcinomas and ∼20 times more likely to develop melanomas as are those with darkly pigmented skin. Skin pigmentation depends not only on the production of melanin by melanocytes but importantly depends on the transfer of that melanin to adjacent keratinocytes and its distribution towards the surface of the skin. Functional melanocytes are essential to this process of course, but keratinocytes also play a crucial role in determining skin color. A recent study (Yoshida et al., 2007) provides important new insights into the role of keratinocytes in determining visible color in different skin phenotypes. More than 120 distinct genes regulate mammalian pigmentation (Bennett and Lamoreux, 2003), working at various levels to determine the development and distribution of melanocytes, their differentiation and their regulation by physiological factors. Great strides have been made in understanding those processes and how they interact to regulate visible pigmentation. Yet none of the pigment genes identified have been associated with defects in melanosome transfer from melanocytes to keratinocytes. One human disease has been associated with defects in melanosome transfer, guttate leucoderma (Jimbow, 1997), and several factors have been identified recently that play roles in the transfer (protease-activated receptor 2 (PAR2) and keratinocyte growth factor (KGF)). Many studies over the years have shown that melanocytes in mono-culture are competent to secrete melanosomes to the extracellular milieu and that this process can be regulated physiologically, e.g. by UV radiation and by alpha-melanocyte stimulating hormone (αMSH). Keratinocytes in mono-culture are competent and efficient in phagocytosing melanosomes from the medium, and again, that process can be regulated physiologically. However, despite many attempts to observe the actual transfer of melanosomes between those two types of cells, either in skin or in artificial skin models, there is no consensus on how that process occurs or is modulated in melanocytes or in keratinocytes (Boissy, 2003; Seiberg, 2001; Van Den Bossche et al., 2006). The biosynthesis of melanin, the biogenesis of melanosomes and the movement of melanosomes to the dendrites of melanocytes are all pretty well characterized at this point, yet the transfer process from melanocytes to keratinocytes remains a 'black box'. Progress on unraveling the mechanism of melanosome transfer is being made in small increments. Earlier studies revealed that melanosome transfer and subsequent distribution of melanosomes in keratinocytes was regulated and differed in skin of various racial/ethnic groups (Gibbs et al., 2000; Minwalla et al., 2001; Okazaki et al., 1976; Yamamoto and Bhawan, 1994). Later studies showed that the process could be mimicked in co-culture models and could be regulated by physiological agents (Virador et al., 2002), but still no light was shed on the actual process involved. Other groups have reported the involvement of ligands (such as KGF) and receptors (such as PAR2) in regulating uptake of melanosomes by keratinocytes (Cardinalli et al., 2005; Greatens et al., 2005; Scott et al., 2001; Seiberg, 2001). Earlier studies by the Boissy group demonstrated that keratinocytes played an integral role in the transfer of melanosomes and determined the way the ingested melanosomes were subsequently distributed (Boissy, 2003; Boissy and Nordlund, 1997; Thong et al., 2003). However, the relatively slow nature of the transfer process, and the limited times for observation of effects in co-culture and in artificial skin models has heretofore hindered investigations of the mechanism(s) involved in melanosome transfer between melanocytes and keratinocytes. Yoshida et al. took the novel approach of establishing a long-term model in which to observe the involvement of different types of cells, and regulators of melanosome transfer, on eventual skin color. They devised a model in which they could supply various combinations of epidermal cells (i.e. melanocytes and keratinocytes) derived from skin of different racial-ethnic origins, and grow them in skin grafts on SCID mice. They could combine cells derived from light-skinned donors and/or dark-skinned donors, place them into grafts on the dorsal skin of SCID mice, and then observe the effects for weeks or months thereafter. Using that model, they found that keratinocytes play a significant role in determining the amount and type of melanin produced by melanocytes, the number of melanosomes that are transferred from melanocytes and their eventual distribution patterns in keratinocytes (i.e. individually or in clusters). This not only proves that keratinocytes are integrally involved in melanosome transfer and are not just inactive bystanders, but also they play a significant role in regulating melanocyte differentiation, in itself an exciting finding. Keratinocytes derived from dark-skinned donors markedly stimulated the expression of melanogenic proteins (e.g. MITF, tyrosinase, Pmel17 and MART1) of melanocytes, regardless of whether the melanocytes were derived from light- or dark-skinned donors. This new model system not only provides important insights into the significant roles of keratinocytes in determining skin color, but provides an important model that should allow further characterization of the system, not only to determine the physiological processes involved in the transfer process per se, but also into the signaling mechanisms by which the keratinocytes help determine melanocyte function. References Bennett, D.C., and Lamoreux, M.L. (2003). The color loci of mice – a genetic century. Pigment Cell Res., 16, 333– 344. Boissy, R.E. (2003). Melanosome transfer to and translocation in the keratinocyte. Exp. Dermatol., 12, 5– 12. Boissy, R.E., and Nordlund, J.J. (1997). Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res., 10, 12– 24. Cardinalli, G., Ceccarelli, S., Kovacs, D., Aspite, N., Lotti, L.V., Torrisi, M.R., and Picardo, M. (2005). Keratinocyte growth factor promotes melanosome transfer to keratinocytes. J. Invest. Dermatol., 125, 1190– 1199. Gibbs, S., Murli, S., De Boer, G., Mulder, A., Mommaas, A.M., and Ponec, M. (2000). Melanosome capping of keratinocytes in pigmented reconstructed epidermis – effect of ultraviolet radiation and 3-isobutyl-1-methyl-xanthine on melanogenesis. Pigment Cell Res., 13, 458– 466. Greatens, A., Hakozaki, T., Koshoffer, A. et al. (2005). Effective inhibition of melanosome transfer to keratinocytes by lectins and niacinamide is reversible. Exp. Dermatol., 14, 498– 508. Jimbow, K. (1997). Tuberous sclerosis and guttate leukodermas. Semin. Cutan. Med. Surg., 16, 30– 35. Minwalla, L., Zhao, Y., Le Poole, I.C., Wickett, R.R., and Boissy, R.E. (2001). Keratinocytes play a role in regulating distribution patterns of recipient melanosomes in vitro. J. Invest. Dermatol., 117, 341– 347. Okazaki, K., Uzuka, M., Morikawa, F., Toda, K., and Seiji, M. (1976). Transfer mechanism of melanosomes in epidermal cell culture. J. Invest. Dermatol., 67, 541– 547. Scott, G., Deng, A., Rodriguez-Burford, C., Seiberg, M., Han, R., Babiarz, L., Grizzle, W., Bell, W., and Pentland, A. (2001). Protease-activated receptor 2, a receptor involved in melanosome transfer, is upregulated in human skin by ultraviolet irradiation. J. Invest. Dermatol., 117, 1412– 1420. Seiberg, M. (2001). Keratinocyte–melanocyte interactions during melanosome transfer. Pigment Cell Res., 14, 236– 242. Thong, H-Y., Jee, S-H., Sun, C-C., and Boissy, R.E. (2003). The patterns of melanosome distribution in keratinocytes of human skin as one determining factor of skin colour. Br. J. Dermatol., 149, 498– 505. Van Den Bossche, K., Naeyaert, J.M., and Lambert, J. (2006). The quest for the mechanism of melanin transfer. Traffic, 7, 769– 778. Virador, V., Muller, J., Wu, X. et al. (2002). Influence of α-melanocyte stimulating hormone and ultraviolet radiation on the transfer of melanosomes to keratinocytes. FASEB J., 16, 105– 107. Yamamoto, O., and Bhawan, J. (1994). Three modes of melanosome transfers in Caucasian facial skin: hypothesis based on an ultrastructural study. Pigment Cell Res., 7, 158– 169. Yoshida, Y., Hachiya, A., Sriwiriyanont, P., Ohuchi, A., Kitahara, T., Takema, Y., Visscher, M.O., and Boissy, R.E. (2007). Functional analysis of keratinocytes in skin color using a human skin substitute model composed of cells derived from different skin pigmentation types. FASEB J., 21, 2829– 2839. Citing Literature Volume20, Issue5October 2007Pages 334-335 ReferencesRelatedInformation

The acquisition of invasive behaviour is the key transition in the progression of benign melanocyte hyperplasia to life threatening melanoma. Understanding this transition and the mechanisms of invasion are the key to understanding why malignant melanoma is such a devastating disease and will aid treatment strategies. Underlying the invasive behaviour is increased cell motility caused by changes in cytoskeletal organization and altered contacts with the extra-cellular matrix (ECM). In addition, changes in the interactions of melanoma cells with keratinocytes and fibroblasts enable them to survive and proliferate outside their normal epidermal location. Proteomic and genomic initiatives are greatly increasing our knowledge of which gene products are deregulated in invasive and metastatic melanoma; however, the next challenge is to understand how these genes promote the invasion of melanoma cells. In recent years new models have been developed that more closely recapitulate the conditions of melanoma invasion in vivo. It is hoped that these models will give us a better understanding of how the genes implicated in melanoma progression affect the motility of melanoma cells and their interactions with the ECM, stromal cells and blood vessels. This review will summarise our current understanding of melanoma invasion and focus on the new model systems that can be used to study melanoma.

Pigment Cell ResearchVolume 20, Issue 5 p. 402-404 Vitiligo-associated multiple autoimmune disease is not associated with genetic variation in AIRE Ying Jin, Ying Jin Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorDorothy C. Bennett, Dorothy C. Bennett Division of Basic Medical Sciences, St George’s, University of London, London, UKSearch for more papers by this authorAnita Amadi-Myers, Anita Amadi-Myers Division of Basic Medical Sciences, St George’s, University of London, London, UKSearch for more papers by this authorPaulene Holland, Paulene Holland Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorSheri L. Riccardi, Sheri L. Riccardi Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorKatherine Gowan, Katherine Gowan Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorPamela R. Fain, Pamela R. Fain Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorRichard A. Spritz, Corresponding Author Richard A. Spritz Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA *Address correspondence to Richard A. Spritz, e-mail: [email protected]Search for more papers by this author Ying Jin, Ying Jin Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorDorothy C. Bennett, Dorothy C. Bennett Division of Basic Medical Sciences, St George’s, University of London, London, UKSearch for more papers by this authorAnita Amadi-Myers, Anita Amadi-Myers Division of Basic Medical Sciences, St George’s, University of London, London, UKSearch for more papers by this authorPaulene Holland, Paulene Holland Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorSheri L. Riccardi, Sheri L. Riccardi Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorKatherine Gowan, Katherine Gowan Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorPamela R. Fain, Pamela R. Fain Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver and Health Sciences Center, Aurora, CO, USASearch for more papers by this authorRichard A. Spritz, Corresponding Author Richard A. Spritz Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA *Address correspondence to Richard A. Spritz, e-mail: [email protected]Search for more papers by this author First published: 06 August 2007 https://doi.org/10.1111/j.1600-0749.2007.00398.xCitations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References Abecasis, G.R., Cherny, S.S., Cookson, W.O., and Cardon, L.R. (2002). Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101. Alkhateeb, A., Stetler, G.L., Old, W. et al. (2002). Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2. Hum. Mol. Genet. 15, 161–167. Alkhateeb, A., Fain, P.R., Thody, A., Bennett, D.C., and Spritz, R.A. (2003). Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their relatives. Pigment Cell Res. 16, 208–214. Alkhateeb, A., Fain, P., and Spritz, R.A. (2005). Candidate functional promoter variant in the FOXD3 melanoblast developmental regulator gene in autosomal dominant vitiligo. J. Invest. Dermatol. 125, 388–391. Barrett, J.C., Fry, B., Maller, J., and Daly, M.J. (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265. Betterle, C., Greggio, N.A., and Volpato, M. (1998). Autoimmune polyglandular syndrome type 1. J. Clin. Endocr. Metab. 83, 1049–1055. Fain, P.R., Gowan, K., LaBerge, G.S., Alkhateeb, A., Stetler, G.L., Talbert, J., Bennett, D.C., and Spritz, R.A. (2003). A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. Am. J. Hum. Genet. 72, 1560–1564. Horvath, S., Xu, X., Lake, S.L., Silverman, E.K., Weiss, S.T., and Laird, N.M. (2004). Family-based tests for association haplotypes with general phenotype data: application to asthma genetics. Genet. Epidemiol. 26, 61–69. Howitz, J., Brodthagen, H., Schwartz, M., and Thompsen, K. (1977). Prevalence of vitiligo: epidemiological survey of the Isle of Bornholm, Denmark. Arch. Dermatol. 113, 47–52. Jin, Y., Mailloux, C.M., Gowan, K., Riccardi, S.L., LaBerge, G., Bennett, D.C., Fain, P.R., and Spritz, R.A. (2007). NALP1 in vitiligo-associated multiple autoimmune disease. New Engl. J. Med. 356, 1216–1225. Laberge, G., Mailloux, C.M., Gowan, K., Holland, P., Bennett, D.C., Fain, P.R., and Spritz, R.A. (2005). Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res. 18, 300–305. Lander, E., and Kruglyak, L. (1995). Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247. Majumder, P.P., Nordlund, J.J., and Nath, S.K. (1993). Pattern of familial aggregation of vitiligo. Arch. Dermatol. 129, 994–998. Martin, E.R., Monks, S.A., Warren, L.L., and Kaplan, N. (2000). A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am. J. Hum. Genet. 6, 146–154. Nath, S.K., Majumder, P.P., and Nordlund, J.J. (1994). Genetic epidemiology of vitiligo: multilocus recessivity cross-validated. Am. J. Hum. Genet. 55, 981–990. Nordlund, J.J., Ortonne, J.P., and Le Poole, I.C.(2006). Vitiligo vulgaris. In The Pigmentary System, J.J. Nordlund, R.E. Boissy, V.J. Hearing, R.A. King, W.S. Oetting, and J.-P. Ortonne, eds. 2nd edn. (Malden, MA: Blackwell Publishing), pp. 551–598. Ramsay, C., Winqvist, O., Puhakka, L., Halonen, M., Moro, A., Kampe, O., Eskelin, P., Pelto-Huikko, M., and Peltonen, L. (2002). Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 11, 397–409. Spritz, R.A. (2007). The genetics of generalized vitiligo and associated autoimmune diseases. Pigment Cell Res. 20, 271–278. Spritz, R.A., Gowan, K., Bennett, D.C., and Fain, P.R. (2004). Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am. J. Hum. Genet. 74, 188–191. Sun, X., Xu, A., Wei, X., Ouyang, J., Lu, L., Chen, M., and Zhang, D. (2006). Genetic epidemiology of vitiligo: a study of 815 probands and their families from south China. Int. J. Dermatol. 45, 1176–1181. Citing Literature Volume20, Issue5October 2007Pages 402-404 ReferencesRelatedInformation

As the ability to detect and define stem cells (SCs) has increased, attention is turning towards the definition of the niche and the identification of the signals that induce SC quiescence or proliferation. The melanocyte stem-niche system, in which the SCs and their progeny occupy geographically distinct domains within the hair follicle, provides one of the best models for studying the complex interplay between environmental cues and transcription factors that underpin cell fate. This review discusses what is known of the origin and molecular characteristics of melanocyte SCs and proposes a series of temporal events that are likely to contribute to the establishment of melanocyte SCs in the hair follicle. We also highlight the possibility of in vitro systems capable of directing cultured melanocytes/melanoblasts to a SC fate in response to specific extrinsiccues.

Of all skin cancers, cutaneous malignant melanoma (CMM) is the most aggressive and the life expectancy of patients with lymphatic or systemic metastases is dramatically reduced. Understandably therefore, scientists and clinicians have focused on improving diagnostic and prognostic techniques. Of these, perhaps the most promising are multimarker real-time RT-PCR and microarray for detection of circulating CMM cells in peripheral blood. While the optimal set of markers is still to be identified that can accurately assess disease severity and progression at all clinical stages of the disease, recent progress has been dramatic. Here we provide an exhaustive review of recent studies in which a variety of markers are assessed. Moreover, the efficacy of the markers relative to clinical stage is discussed in light of experimental findings. From these studies, it is apparent that researchers are now much closer to defining a set of markers of circulating cells that can be utilized in routine diagnostic tests.

When looking at vitiligo skin, the disease seems clinically at least simpler than other common chronic skin disorders, such as atopic dermatitis or psoriasis. There is only a visible loss of pigmentation, and opposite to these other chronic skin conditions, inflammation is lacking. When taking a biopsy of vitiliginous skin, the evidence of inflammation is usually scarce or absent, even though some reports support a marginal infiltration of T cells (Van den Wijngaard et al., 2000). The microscopic features are dominated by a loss of melanocytes, without clear destructive process targeting those cells, and foci of pigment cell loss without inflammatory infiltrates have been documented in normal looking skin in generalized (non-segmental) vitiligo (Pretti Aslanian et al., 2007). The next question is then: why do melanocytes leave the epidermis and/or hair follicles? This question has generated several speculations (reviewed in Dell'anna and Picardo, 2006; Gauthier et al., 2003; Taieb, 2000), based on clinical or experimental data, but without definitive supporting evidence. As a consequence of this absence of basic understanding of the disease, therapies do not meet the patient's needs (Whitton et al., 2006). The apparently simple problem of vitiligo is indeed one of the most challenging ones in dermatology and medicine. A good angle of attack to the problem is obviously lacking. Other common chronic disorders including skin disorders have benefited from the genetic angle. In 2006, a breakthrough was made in atopic dermatitis and related atopic disorders, a field also characterized by very contrasted opinions about pathophysiology and therapeutic options. A skin inherited basis, with a loss of function of a gene encoding filaggrin, a stratum corneum precursor protein, was found in 30–40% of cases of European descent individuals with the disorder (Palmer et al., 2006). Similar progress is expected to follow for psoriasis, which has a strong inherited component, and part of its heritability is probably also situated within the epidermal differentiation complex at 1q21 close to filaggrin (Cookson et al., 2001). However, when comparing common chronic skin disorders for monozygous twin concordance, an excellent marker of the inherited component in complex disorders, atopic dermatitis and psoriasis have definitely a more inherited profile than vitiligo: only 23% concordance for vitiligo (Alkhateeb et al., 2003), versus 35–56% in psoriasis (Brandrup et al., 1982; Duffy et al., 1993) and up to 72% in atopic dermatitis (Schultz Larsen, 1993). Furthermore, according to genome-wide linkage analyses for the generalized vitiligo phenotype performed in populations of various ethnic backgrounds, the major inherited loci are not the same (Chen et al., 2005; Fain et al., 2003). Thus, the genetic angle of attack has certainly intrinsic weaknesses in vitiligo research but, in derivation of it, the recent paper by the group of Spritz (Jin et al., 2007) offers an unexpected research avenue for vitiligo-associated autoimmune/inflammatory disorders. This study is based on previous reports of the same group that have shown a linkage between a locus on chromosome 17p13 and multiple autoimmune disease associated with vitiligo. This locus is not linked with vitiligo occurring in isolation. Scanning with SNPs (single-nucleotide polymorphims) the 11.3 cM interval of 6.19 Mb containing the putative autoimmune vitiligo gene at 17p13, the authors found one haplotype encoding the proximal coding region and the extended promotor region of the NALP1 gene (encoding NACHT leucine-rich-repeat protein 1), which shows a significant but not considerable association with vitiligo and vitiligo-associated autoimmune diseases (odds ratio of less than 2). Further analyses led to the conclusion that two independent variants of the NALP1 region are associated with an increased risk of vitiligo-associated autoimmune/inflammatory diseases, one situated on the NALP1 gene, and the other upstream in a region involving the gene promoter. The functional significance of these genetic variants is still unknown. How much will this change our current (absence of) understanding of vitiligo? NALP1 is a NOD (nucleotide-binding oligomerization domain protein)-like receptor, a family of pattern recognition receptors for microorganisms, apoptotic fragments or cell debris, which also includes NOD2. Interestingly, variants of NOD2 are associated with Crohn's disease, an inflammatory intestinal barrier disease (Hugot et al., 2001). In Crohn's disease, variant NOD2 alleles cause a loss of physiological tolerance to commensal bacteria. As a consequence, immune responses develop that activate immunocompetent cells, resulting in the secretion of proinflammatory mediators that cause mucosal breaks and ulcerations. If NALP1 is physiologically close, its still unknown role in skin barrier is unlikely to provoke such a dramatic scenario causing a loss of pigment cells, because this would be clinically and histologically detectable. NALP1 is immunohistochemically found in epidermis within Langerhans cells (Kummer et al., 2007), but more precise studies focusing on pigment cells are lacking. NALP1 and 3 are part of cytoplasmic complexes called inflammasomes that regulate the activation of caspases which in turn convert proinflammatory cytokines into their active forms. Mutant NAPL3 phenotypes are known and are also clearly inflammatory causing disorders such as Muckle–Wells syndrome (Agostini et al., 2004). Several lines of evidence suggest that the skin itself is important in the primary pathogenesis of vitiligo such as Koebner's phenomenon, the more severe presentation of segmental vitiligo when associated with generalized vitiligo, so that to sum up our current perception, some fragility in the epidermal melanin unit, which may have an inherited component, leads to a chronic melanocytorrhagy (Gauthier et al., 2003). However, as stated before, inflammation is clearly not a major part of the disease. Thus, if the inflammasome story holds true in vitiligo in the context of a personal or family history of autoimmune disorders, my guess is that it could help trigger or enhance the autoimmune part of the disease, which may involve initial contacts between melanocytes or melanocyte fragments and NALP1-positive Langerhans, rather than being an initial factor in which a systemically dysregulated innate immunity would get rid of epidermal melanocytes as a priority. As noted by the authors of the NEJM paper (Jin et al., 2007), the NALP1 discovery is important to test new treatment options such as interleukin-1 (IL-1) receptor antagonists in autoimmune vitiligo and the group of vitiligo-related autoinflammatory disorders. This would be possible via the possible impairment of the NALP1-dependent regulation of the activity of caspases 1 and 5 which in turn modulate IL-1β activity. However, it is tempting to speculate that for the more common non-segmental vitiligo phenotype occurring in isolation, without demonstrated autoimmunity, there is an intervention of a low key activation of the huge reservoir of IL-1β which is found in the stratum corneum. For instance, mechanical trauma might be such an environmental candidate factor leading to events that could subsequently destabilize the anchoring of basal melanocytes, without creating clinical or histological inflammation. In the epidermis, IL-1β is produced as a biologically inactive 31-kDa precursor, which is converted to the active 18-kDa form by proteolytic processing. Keratinocytes do not express the active form of the specific IL-1β-converting enzyme. Thus, the activation in situ of IL-1β remains elusive. Nylander-Lundqvist and Egelrud (1997) have already shown that IL-1β activation in human epidermis can occur via an alternative mechanism involving stratum corneum chymotryptic enzyme (SCCE or kallikrein 7), a serine protease specifically expressed in keratinizing squamous epithelia. I would thus propose to take a look at this proposed alternative pathway of activation in vitiligo, which, if implicated, would support the view that many events occurring in skin physiology and disease are under the control of the most differentiated part of the epidermis, the stratum corneum (Elias et al., 1999). This would also fit the idea applicable to common skin disorders that the evidence is frequently closer to our eyes than expected due to complex speculations, as highlighted in Edgar Allan Poe's famous short story, the purloined letter (Taieb, 2007).

Mutations in the BRAF oncogene occur in the majority of melanomas, leading to the activation of the mitogen-activated protein kinase pathway and the transcription of downstream effectors. As BRAF and its effectors could be good melanoma therapy targets, defining the repertoire of genes that are differentially regulated because of BRAF mutational activation is an important objective. Towards this goal, we and others have attempted to determine whether a BRAF mutation-associated gene expression profile exists. Results have been mixed, with some groups reporting a BRAF-signature and another group not. Here we resolve this issue and confirm that while gene-by-gene correlations fail to reveal a specific gene(s) whose expression correlates with BRAF status, a BRAF signature can be distinguished by analysis of global expression patterns. Specifically, we have here applied support vector machine (SVM) analysis to Affymetrix microarray data from a panel of 63 melanoma cell lines. SVMs found a BRAF signature in training samples and predicted BRAF mutation status with high accuracy (AUC=0.840) in the remaining samples. We verified this is a generalized BRAF signature by repeating the analysis in three published microarray datasets, and again found that SVMs predicted BRAF mutation well (Philadelphia: AUC=0.788; Zurich: AUC=0.688; Mannheim: AUC=0.686). An ensemble of 300 SVMs trained on our data also predicted BRAF mutation status in two of the three published datasets (Philadelphia AUC=0.778; Zurich AUC=0.719; Mannheim AUC=0.564). Taken together, these data support the existence of a BRAF mutation-specific expression signature.

Pigment Cell ResearchVolume 20, Issue 1 p. 36-40 Mammalian paramutation: a tail's tale? Heinz Arnheiter, Heinz Arnheiter Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, MD, USA. e-mail: ha3p@nih.govSearch for more papers by this author Heinz Arnheiter, Heinz Arnheiter Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, MD, USA. e-mail: ha3p@nih.govSearch for more papers by this author First published: 17 November 2006 https://doi.org/10.1111/j.1600-0749.2006.00351.xCitations: 11Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume20, Issue1February 2007Pages 36-40 RelatedInformation

Common generalized vitiligo is an acquired depigmenting disorder characterized by a chronic and progressive loss of melanocytes from the epidermis and hair follicles. We previously proposed a new theory that vitiligo involves the chronic detachment and transepidermal loss of melanocytes caused by autoimmune, neural and impaired redox mechanisms associated with mechanical trauma. In this study, we reconstructed epidermis on dead de-epidermized dermis with normal and/or non-segmental non-lesional vitiligo (NSV) cells and tested catecholamines or sera or hydrogen peroxide. Under unstressed conditions, the number of melanocytes located in the basal layer was significantly lower in reconstructs made with melanocytes from non-lesional NSV skin and normal keratinocytes compared with controls made with autologous normal melanocytes. The number of non-lesional NSV melanocytes was even lower in reconstructs made with keratinocytes from non-lesional NSV skin. Epinephrine and H(2)O(2) could trigger the transepidermal loss of normal and vitiligo melanocytes. Some sera induced melanocyte detachment but without any clear correlation with disease activity in the donors. In conclusion, our results are the first step to obtaining a reproducible melanocytorrhagic model in vitro with some of the stressors investigated. They support the hypothesis that NSV melanocytes have an intrinsic defect, which limits their adhesion in a reconstructed epidermis, with an enhancer effect of the vitiligo keratinocyte milieu.

The Wnt signaling pathway controls cell fate determination in neural crest cells, which give rise to melanocytes (Dorsky et al., 1998). Activation of Wnt signaling inhibits β-catenin degradation, resulting in its nuclear accumulation. In the nucleus, β-catenin can have dual functions; it can activate transcription of LEF/TCF target genes when bound to p300 HAT, or represses transcription when tethered to HDAC1 (Billin et al., 2000). Nuclear localization of β-catenin is found in ∼30% of human melanoma specimens (Larue and Delmas, 2006). Targets of β-catenin in melanocytes and melanoma cells include the transcription factors MITF and Brn2, and the pigment gene dopachrome tautomerase (dct) (Larue and Delmas, 2006). In recent years, it has become clear that Wnt signaling can also function via β-catenin-independent pathways. These non-canonical pathways include: 1) calcium/calmodulin-dependent kinase II (CAMKII), and protein kinase C (PKC), 2) phospholipase C (PLC) and phosphodiesterase (PDE), and 3) a pathway similar to the planar polarity in Drosophila that activates the Jun-N-terminal kinase (Kikuchi et al., 2007). There are at least 19 Wnts and 10 Frizzled receptors. Wnt5a belongs to the so-called intermediate or non-transforming Wnt proteins of mouse mammary epithelial cells that also include Wnt5b, Wnt2, Wnt4, Wnt6, Wn7b and Wnt11 (Kikuchi et al., 2007). An early gene expression profiling study found Wnt5a/PKC to be associated with aggressive melanoma behavior (Bittner et al., 2000). Using Wnt5a overexpression in melanoma cell lines and a small sample of paraffin-embedded nevi, primary invasive and metastatic melanoma specimens, a follow up study demonstrated that Wnt5a activates PKC and stimulates motility and invasion of metastatic melanoma (Weeraratna et al., 2002). Supporting these results, Wnt5a expression also correlates with aggressive gastric cancer by facilitating cell migration and invasion (Kurayoshi et al., 2006). In a new study, the Weeraratna group used overexpression and down-regulation of Wnt5a, and microarray analysis to demonstrate that Wnt5a/PKC stimulates melanoma cell motility via induction of genes involved in the epithelial to mesenchymal transition (EMT) of carcinomas including up-regulation of vimentin and Snail (a repressor of E-cadherin), and down-regulation of E-cadherin (Dissanayake et al., 2007). PKC consists of ten isoforms with variable regulatory regions and conserved catalytic domains. Several isoforms play complex and sometimes opposite roles in melanogenesis, proliferation and transformation of human melanocytes. Numerous studies have consistently shown that phorbol esters have dual functions as growth promoters of normal melanocyte proliferation and as growth inhibitors of melanoma cells via the activation of different sets of PKC isoforms (Oka and Kikkawa, 2005). Using UACC1273 melanoma cells and derivatives, Dissanayake et al. demonstrated that phorbol esters increase PKC activity, expression of Snail and cell migration, whereas the PKC inhibitor Go6983 had the opposite effect. Thus both, Wnt5a and PKC appear to be critical for the invasion properties of melanoma cells. Malignant melanoma is a paradigm of the complexity and heterogeneity of human tumors. Thus, it is not surprising that other studies contradict some results by Dissanayake et al. For example, two papers demonstrated that Wnt5a and its receptor Frizzled are highly expressed in benign nevi but significantly reduced in melanomas (Pham et al., 2003; Bachmann et al., 2005). Also, a recent high–throughput study that compared gene expression profiles of cutaneous malignant melanomas (CMM) in the vertical growth phase that progressed into metastatic disease with vertical growth phase CMM without evidence of metastasis (after a median follow-up of 116 months) did not identify Wnt5a among the 243 differentially expressed genes (Alonso et al., 2007). These authors also found strong evidence of EMT signatures; 40 such genes were differentially expressed including N-cadherin, SPARC (also a repressor of E-cadherin) and osteopontin but not Snail. Technical issues and/or more complex reasons including variability in tumor thickness, ulceration and level of invasion between the tumors used in the different studies could explain the conflictive data described above. In conclusion, the studies discussed herein and previous data (Kuphal et al., 2005) support a critical role of EMT in the development of melanoma metastasis. Yet, adding to the complexity of melanoma the Sharpless group recently identified a molecularly distinct melanoma subtype that neither displays N-RAS or B-RAF mutations, nor requires EMT for progression but exhibits p53 inactivation (Shields et al., 2007).

Since the cloning of the Drosophila gene in the 1980s, decades of research have sought to dissect the intricacies of the mammalian Notch signaling cascade. The intrigue of this pathway undoubtedly lies in its ability to influence diverse cellular processes, including differentiation, cell fate, homeostasis, survival, proliferation and angiogenesis. Based on its evolutionary conservation and its fundamental role in development, it is not surprising that deregulation of the Notch signaling pathway can result in neoplastic growth. While originally of particular interest to immunologists based on its chief role in influencing T-cell fate decisions and tumor oncogenesis in T-cell acute lymphoblastic leukemia, pigment cell biologists have recently taken notice of the Notch cascade based on studies suggesting the importance of this pathway in regulating melanocyte stem cell survival and melanoma progression. We will review the Notch signaling literature as it relates to skin homeostasis, melanocytic stem cells and melanoma tumorigenesis.

It is sad fact that despite the enormous effort over decades that has been put in to trying to find an effective treatment for metastatic melanoma, the disease remains stubbornly uncooperative. Although combination drug therapies, including those based on trying to target BRAF, have had limited success in extending lifespan, the ultimate goal of an effective cure for the disease remains as elusive as ever. What can be done? Clearly, the solution is not going to be simple or more progress would have been made already in treating the disease. The answer is likely to lie in a combination of four things: gaining a deep understanding of the disease at the molecular level; animal models that reflect the human disease as accurately as possible; a recognition that each tumor may contain variable proportion of cells with different properties, e.g. stem cells, proliferating cells and differentiated cells, that may respond differentially to anti-melanoma-drugs and which are likely to switch between different states in response to a changing microenvironment; and close cooperation between the clinical and basic scientists. Each alone will make only a small difference, but combined, may represent our best hope for dealing with this disease. The communication between clinical and basic scientists has historically been very limited. In part, this is because while basic science tries to understand the disease better so that novel approaches to therapy may be developed in the future, clinicians are understandably under pressure to deal with the problem that faces them each day: the prospect of an effective drug in 10 years time is not much use to a patient today. Yet, if we are to make a difference, basic and clinical science must not only communicate, they must understand each other and understanding requires substantial effort. With that thought in mind it is heart-warming that the ambition of the SMR is not only to promote high quality research, but also to enhance the communication between the various melanoma research fields. It is much needed. On top of that, there is also a lack of communication between those interested in fundamental aspects of pigment cell biology and those with a more disease oriented focus. This is also to be lamented. The propensity of melanoma to metastasise rapidly most likely reflects the intrinsic migratory ability of melanoblasts during development. Melanin chemistry, at first sight might appear irrelevant to melanoma, yet the capacity of melanin to act as a sink for small molecules poses particular problems for effective drug delivery. Just as there is a clear need for discussion between clinicians and basic melanoma scientist, the same is true of melanoma and pigment cell biologists. There is much to learn from each other and this journal, soon to be renamed ‘Pigment Cell & Melanoma Research’, is intended to act as focus for the entire pigment cell field. Given the association of the journal with the SMR and the New York melanoma meeting, this issue is designed to highlight some of the points mentioned above and contains a series of reviews that touch on basic melanoma biology. That from Keith Hoek highlights the progress and pitfalls that have been made in understanding melanoma progression based on gene array analysis; the review from Beermann and Larue illustrates the various animal melanoma models available; Herlyn’s review on Notch touches on the role of this key molecule in both melanoma progression and in development; and Ze’ev Ronai reviews progress in understanding the role and regulation of the key transcription factor ATF2 in melanoma. The breadth of topics covered reflects both the complexity of the disease as well as the considerable progress made. Yet, although there is no doubt that the powerful tools being applied to melanoma research will yield results, the challenge remains to get the insights generated translated into something that will make a real difference in the clinic. There is much work to be done.

Pigment Cell ResearchVolume 20, Issue 4 p. 309-310 Response to Slominski et al. Rutao Cui, Rutao Cui Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorHans R. Widlund, Hans R. Widlund Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorErez Feige, Erez Feige Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorJennifer Y. Lin, Jennifer Y. Lin Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorVivien E. Igras, Vivien E. Igras Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorJohn D’Orazio, John D’Orazio Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorClaire Y. Fung, Claire Y. Fung Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorCarl F. Schanbacher, Carl F. Schanbacher Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorScott R. Granter, Scott R. Granter Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorDavid E. Fisher, Corresponding Author David E. Fisher *Address correspondence to David E. Fisher, e-mail: [email protected]Search for more papers by this author Rutao Cui, Rutao Cui Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorHans R. Widlund, Hans R. Widlund Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorErez Feige, Erez Feige Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorJennifer Y. Lin, Jennifer Y. Lin Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorVivien E. Igras, Vivien E. Igras Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorJohn D’Orazio, John D’Orazio Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorClaire Y. Fung, Claire Y. Fung Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorCarl F. Schanbacher, Carl F. Schanbacher Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorScott R. Granter, Scott R. Granter Melanoma Program in Medical Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USASearch for more papers by this authorDavid E. Fisher, Corresponding Author David E. Fisher *Address correspondence to David E. Fisher, e-mail: [email protected]Search for more papers by this author First published: 11 July 2007 https://doi.org/10.1111/j.1600-0749.2007.00391.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume20, Issue4August 2007Pages 309-310 RelatedInformation

Generalized vitiligo is an acquired disorder in which patches of depigmented skin, overlying hair, and oral mucosa result from progressive autoimmune loss of melanocytes from the involved areas. Although vitiligo is perhaps the most common pigmentary disorder, insufficiently clear clinical definition of the disorder and lack of a good laboratory animal model have inhibited progress in understanding its pathobiology, its environmental triggers, and in developing specific and effective therapeutic approaches. Vitiligo results from a complex interaction of environmental, genetic, and immunologic factors, which ultimately contribute to melanocyte destruction, resulting in the characteristic depigmented lesions. In the past few years, studies of the genetic epidemiology of generalized vitiligo have led to the recognition that vitiligo is part of a broader, genetically-determined, autoimmune/autoinflammatory diathesis. Attempts to identify genes involved in vitiligo susceptibility have involved both allelic association studies of candidate genes and genome-wide linkage analyses to discover new genes, and these studies have begun to shed light on the mechanisms of vitiligo pathogenesis. It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel therapeutic and prophylactic targets for future approaches to the treatment and prevention of vitiligo and its associated autoimmune diseases.

For the vast majority of cancers at least some progress in effective treatment has been forthcoming over the years. Not so for melanoma. This highly aggressive and increasingly common cancer can be cured by surgical excision at an early stage, but metastatic melanoma remains highly refractive to therapy. It is increasingly clear that melanoma is a complex disease in which pathways critical for melanocyte development have been subverted to promote proliferation, and that the normal pro-senescence mechanisms that defend us against cancer progression have been suppressed. In recent years significant breakthroughs have been made in identifying the genetic lesions that underpin the genesis of melanoma, most notably those that lead to activation of BRAF or NRAS and suppression of the Rb1 pathway. Yet, as highlighted in the review from Tanja Rothhammer and Anja Bosserhoff, the contribution of epigenetic changes, in which alterations in chromatin organization and modification as well as DNA-methylation patterns affect gene expression without alterations to the DNA sequence, is increasingly recognized as a significant factor in disease progression. The catalogue of known epigenetic modifications in melanoma and potential strategies directed towards modifying the melanoma epigenome are discussed. Although there is an urgent need for novel and effective therapeutic strategies for melanoma, equally important is the ability to detect and identify metastatic and metastasising melanoma cells. This may not be as straightforward as it might seem. While more differentiated, pigmented lesions my be readily detected, what markers will be effective for melanoma cells circulating in the bloodstream, an indicator of metastatic disease that may not be immediately apparent. The current repertoire of melanoma markers includes the microphthalmia-associated transcription factor, Mitf, and a range of proteins produced from genes that are Mitf targets, such as tyrosinase and melan-a. Yet increasing evidence suggests that melanomas may generate melanoma ‘stem cells’ and that these may be Mitf-negative and therefore, like natural melanocyte stem cells, lack all common markers of the melanocyte lineage. In the future it will be imperative to generate markers that will detect such melanoma stem cells, but for now the advantages and disadvantages of the wide range of melanoma markers currently in use are comprehensively reviewed by Melanie Ziman. For a long time role of calcium in signalling in pigment cells has received perhaps less attention that it deserves. The results presented in the paper from Bush and Simon highlight the fact that melanin has the potential to bind calcium with an affinity that would be consistent with it performing a key role in regulating calcium homeostasis in the cell. Several recent papers have highlighted the key role played by calcium within pigment cells, in melanosome transport for example, or the interesting work on the golden gene slc24a5, that appears to be a melanosome-associated ion exchanger implicated in uptake of calcium into the melanosome. Given the phenotype of zebrafish bearing golden mutations and the potential of this gene for regulation of human pigmentation, an interesting question arising from the Bush and Simon paper is whether intra-melanosome calcium levels might also play major role in signalling to the cell that a mature melanosome has been formed. One of the delights of being Editor-in-Chief of Pigment Cell Research is that I get to choose the cover for each issue. Usually the cover image is provided by a member of the scientific community and frequently represents a striking immunofluorescence image of pigment cells in culture or during development. Occasionally the cover shows the natural pigmentation pattern of a wild animal, the image provided by Rich Spritz of the cheetah in the Masai Mara on the cover of the December issue for example. But the deserved winner of the 2006 cover image of the year this time is not a scientist, but an artist: Pascale Pollier, who designed and made the melanocyte sculpture that graced the October cover. This remarkable piece of work caught the imagination of the voters and received twice as many votes as the next most popular image, the cheetah. It is a just reward for an artist who invested many months in bringing this beautiful fusion of art and science to fruition. For once the usual prize, a year's free subscription to the journal seems inappropriate. Instead I have asked Pascale to produce another cover image and use her talent as an artist to depict the intrinsic splendour of pigment cells. Art and science usually lead independent existences, but of all cell types, it seems to me that the pigment cell that brings so much beauty to life, seems most suited to bridging the chasm that runs between art and science. It is with great sadness that I bring to the attention of all interested in pigmentation and pigment cells, the deaths of two pioneers in the world of pigment cell biology: Mac Hadley, a pioneer in the field of melanocortins, shockingly murdered in his own home in Arizona by a burglar; and Aaron Lerner, who discovered melantonin and MSH, who died suddenly of a heart attack aged 87 a short time ago. We all are indebted to their contribution to pigment cell biology and I anticipate publishing obituaries for both in an upcoming issue of this journal.

Pigment Cell ResearchVolume 20, Issue 3 p. 225-227 Polymorphisms in the genes for oculocutaneous albinism type 1 and type 4 in the German population Christine Zühlke, Corresponding Author Christine Zühlke Institut für Humangenetik der Universität Lübeck, 23538 Lübeck, Germany *Address correspondence to Institut für Humangenetik, e-mail: [email protected]Search for more papers by this authorCarolin Criée, Carolin Criée Institut für Humangenetik der Universität Lübeck, 23538 Lübeck, GermanySearch for more papers by this authorTimo Gemoll, Timo Gemoll Institut für Humangenetik der Universität Lübeck, 23538 Lübeck, Germany Contributed equally to this work.Search for more papers by this authorThomas Schillinger, Thomas Schillinger Institut für Humangenetik der Universität Lübeck, 23538 Lübeck, Germany Contributed equally to this work.Search for more papers by this authorBarbara Kaesmann-Kellner, Barbara Kaesmann-Kellner Augenklinik der Universität des Saarlandes, 66421 Homburg Saar, GermanySearch for more papers by this author Christine Zühlke, Corresponding Author Christine Zühlke Institut für Humangenetik der Universität Lübeck, 23538 Lübeck, Germany *Address correspondence to Institut für Humangenetik, e-mail: [email protected]Search for more papers by this authorCarolin Criée, Carolin Criée Institut für Humangenetik der Universität Lübeck, 23538 Lübeck, GermanySearch for more papers by this authorTimo Gemoll, Timo Gemoll Institut für Humangenetik der Universität Lübeck, 23538 Lübeck, Germany Contributed equally to this work.Search for more papers by this authorThomas Schillinger, Thomas Schillinger Institut für Humangenetik der Universität Lübeck, 23538 Lübeck, Germany Contributed equally to this work.Search for more papers by this authorBarbara Kaesmann-Kellner, Barbara Kaesmann-Kellner Augenklinik der Universität des Saarlandes, 66421 Homburg Saar, GermanySearch for more papers by this author First published: 16 May 2007 https://doi.org/10.1111/j.1600-0749.2007.00377.xCitations: 3 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References Fukai, K., Holmes, S.A., Lucchese, N.J., Siu, V.M., Weleber, R.G., Schnur, R.E., and Spritz, R.A. (1995). Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism. Nat. Genet. 9, 92– 95. Graf, J., Hodgson, R., and Van Daal, A. (2005). Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation. Hum. Mutat. 25, 278– 284. Inagaki, K., Suzuki, T., Shimizu, H. et al. (2004). Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan. Am. J. Hum. Genet. 74, 466– 471. Inagaki, K., Suzuki, T., Ito, S., Suzuki, N., Fukai, K., Horiuchi, T., Tanaka, T., Manabe, E., and Tomita, Y. (2005). OCA4: evidence for a founder effect for the p.D157N mutation of the MATP gene in Japanese and Korean. Pigment Cell Res. 18, 385– 388. Inagaki, K., Suzuki, T., Ito, S. et al. (2006). 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Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism. Hum. Mutat. Mutation in Brief #719, 23, 630– 631. Park, S.K., Lee, K.H., Park, K.C., Lee, J.S., Spritz, R.A., and Lee, S.T. (1997). Prevalent and novel mutations of the tyrosinase gene in Korean patients with tyrosinase-deficient oculocutaneous albinism. Mol. Cells 7, 187– 191. Passmore, L.A., Käsmann-Kellner, B., and Weber, B.H.W. (1999). Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population. Hum. Genet. 105, 200– 210. Rundshagen, U., Zühlke, Ch., Opitz, S., Schwinger, E., and Käsmann-Kellner, K. (2004). Mutations in the MATP-gene in five German patients affected by oculocutaneous albinism type 4. Hum. Mutat. 23, 106– 110. Spritz, R.A., Oh, J., Fukai, K. et al. (1997). Novel mutations of the tyrosinase (TYR) gene in type I oculocutaneous albinism (OCA1). Hum. Mutat. 10, 171– 174. Yuasa, I., Umetsu, K., Watanabe, G., Nakamura, H., Endoh, M., and Irizawa, Y. (2004). MATP polymorphisms in Germans and Japanese: the L374F mutation as a population marker for Caucasoids. Int. J. Legal Med. 118, 364– 366. Zühlke, Ch., Dalski, A., Kaufmann, M., Opitz, S., Lipka, A., Rundshagen, U., Schwinger, E., and Käsmann-Kellner, B. (2004). Molecular analysis in 163 unrelated patients with albinism: Mutations in the genes for OCA1, OCA2, OCA3, and OCA4. Eur. J. Hum. Genet. 12(Suppl. 1), 229. Citing Literature Volume20, Issue3June 2007Pages 225-227 ReferencesRelatedInformation

The terminal differentiation of melanocytes is associated with the transcriptional activation of genes responsible for pigment production such as tyrosinase. Pigment cell-specific transcription factors, such as Mitf, as well as specific proximal and distal regulatory elements (DRE) are implicated in the tight control of tyrosinase expression during development and adulthood. Proper tyrosinase expression in melanocytes depends upon the presence of a DRE that is located at -15 kb and provides enhancer activity via a central element termed core-enhancer. In this report, we show that the transcription factors Sox10, Mitf and USF-1 are able to activate the core-enhancer in luciferase reporter assays. Comparative sequence analysis identified evolutionarily motifs resembling Sox10 binding sites that were required for full enhancer activity in melanoma cells and in tyrosinase::lacZ transgenic mice. Sox10 was able to bind the DRE in vitro and mutation of the conserved motifs abolished the enhancer transactivation mediated by Sox10. In addition, two highly conserved CAGCTG E-box motifs were identified that were also required for enhancer activity and for transactivation by Mitf. The results suggest that Sox10 directly, and Mitf, most likely indirectly, activate the tyrosinase enhancer, underlining the contribution of Sox10 to tyrosinase gene regulation in melanocytes.

It is generally accepted that human cancer is a resultof genetic mutations in molecular pathways controllingprocesses that normally harness the capacity for prolif-eration and survival. An emerging picture has begun toevolve from our understanding of these particular path-ways as they become disrupted in various cancers, in afashion which shows significant lineage-dependence.Cutaneous malignant melanoma, the most commonform of melanoma in man, appears to invariably harbormutations leading to activation of the canonical MAPK-pathway wherein the oncogene BRAF is found activatedin approximately 70% of all melanomas (Davies et al.,2002) as well as benign nevi (Pollock et al., 2003) andcorrespondingly NRAS in another 25% (Demunteret al., 2001) leaving only a small fraction unaccountedfor. In addition, disruption of the pRB-pathway throughloss of pRB, mutation or amplification of CDK4, amplifi-cation of CCND1, missense mutation or deletion of theINK4A-locus is similarly common. However, contrastingmany other human malignancies, melanomas exhibit astrikingly low frequency of canonical p53-mutations,amounting to approximately 20–25% of all cases(Ragnarsson-Olding et al., 2002). This is particularlynotable because of the discordance between the p53’swild-type status and the near-uniform relative refractori-ness of melanomas to numerous triggers of apoptosis,including cytotoxic chemotherapeutic agents. Addition-ally, disruption of the TP53-pathway through amplifica-tion of the HDM2 oncogene occasionally occurs, but itsupstream inhibitor ARF, the alternative product of theINK4A-locus (Kamijo et al., 1997), is a well-known mela-noma tumor-suppressor whose loss together withCDKN2A⁄p16 is relatively common during melanoma-genesis. It is broadly accepted that ARF functions toinhibit MDM2⁄HDM2, the canonical negative regulatorof p53, in mouse and man while there are additionalARF-interacting proteins that may execute importantfunctions various settings of tumorigenesis (Sherr,2006). The common occurrence of wild-type p53together with ARF (and CDKN2A⁄p16) deficiency in mel-anoma has appropriately raised the prospect of a thera-peutic opportunity based upon reactivating p53-function,to which end multiple lead drugs are in various stagesof development.In a recently published study, Merlino and colleagues(Ha et al., 2007) have utilized a powerful genetic modelof murine melanoma to assess the functional roles ofp53 and ARF in murine melanoma-genesis. Their dataclearly demonstrate p53-independent tumor suppressiveactivity of ARF- an observation which carries importantimplications for therapeutic targeting⁄activation of p53in melanoma patients.In this study, Ha et al. employ an established mousemodel that develops UV-induced cutaneous melanomaas well as rhabdomyosarcoma (RMS) via transgenicexpression of hepatocyte growth factor⁄scatter factor(Noonan et al., 2001), the ligand for the cMET receptortyrosine kinase. Merlino et al. previously showed thatmelanoma latency following UV irradiation was signifi-cantly reduced when the transgenic mice were crossedinto an INK4A⁄ARF-null background, suggesting thatloss of both the TP53- (through ARF) and pRB- (throughCDKN2A⁄p16) pathways likely contribute to develop-ment of UV-induced cutaneous melanoma. In this study,the authors have overlaid a more refined approach, ofseparating the functions of the two products from theINK4A-locus. They observe that ARF-nullizygosity exhib-its nearly the same frequency and timing of RMS devel-opment as genetic ablation of both products. Similarly,p53-nullizygousity exhibited similar frequency and timingas ARF-alone for induction of RMS, thus consistent withthe predicted role of the ARF-(MDM2)-p53-pathway fortumor suppression. Importantly, however, UV-inducedmelanoma incidence in these transgenic animalsshowed dependence on both CDKN2A and ARF statuswhereas p53-nullizygousity had no overt effect, suggest-ing that ARF tumor suppressor function is mechanisti-cally distinct from p53-function. The importance of thismelanoma-specific behavior is underscored by the dif-ferences seen in RMS tumors within the same geneticmodel. Interestingly, in a UV-independent RAS-driventransgenic model, CDKN2A, ARF and p53 all displayedimportant contributions as suppressors of melanomaincidence (Bardeesy et al., 2001; Sharpless and Chin,

Pigment Cell ResearchVolume 20, Issue 4 p. 307-308 Does p53 regulate skin pigmentation by controlling proopiomelanocortin gene transcription? Andrzej Slominski, Corresponding Author Andrzej Slominski Department of Pathology, University of Tennessee HSC, Memphis, TN, USA *Address correspondence to Andrzej Slominski, e-mail: [email protected]Search for more papers by this authorDesmond J. Tobin, Desmond J. Tobin Medical Biosciences Research, School of Life Sciences, University of Bradford, Bradford, UKSearch for more papers by this authorRalf Paus, Ralf Paus Department of Dermatology, University of Luebeck, Luebeck, GermanySearch for more papers by this author Andrzej Slominski, Corresponding Author Andrzej Slominski Department of Pathology, University of Tennessee HSC, Memphis, TN, USA *Address correspondence to Andrzej Slominski, e-mail: [email protected]Search for more papers by this authorDesmond J. Tobin, Desmond J. Tobin Medical Biosciences Research, School of Life Sciences, University of Bradford, Bradford, UKSearch for more papers by this authorRalf Paus, Ralf Paus Department of Dermatology, University of Luebeck, Luebeck, GermanySearch for more papers by this author First published: 11 July 2007 https://doi.org/10.1111/j.1600-0749.2007.00390.xCitations: 15Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume20, Issue4August 2007Pages 307-308 RelatedInformation