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New Perspectives on Melanoma_ The Role of PAX3

Notably binding to the mitf promoter requires both

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Unformatted text preview: . The Dct promoter region contains an Mitf binding site (M‐box) directly adjacent to upstream Lef1 binding sites [19,185,187]; Mitf and Lef1 act in synergy to activate the Dct promoter [72]. Pax3 and Mitf share the same binding site within the Dct promoter, and compete for occupancy [19]. In summary, the hierarchy of melanocyte‐specific gene activation (Figure 2.2B) proposed by Opdecamp and colleagues (1997) suggests that in committed melanoblasts, Pax3 and Sox10 synergistically induce Mitf expression. Mitf and Sox10 then cooperate to immediately activate expression of Dct. Induction of Tyr and TRP­1 by Mitf follows a few days later. Expression of most of the melanogenic enzyme genes, Tyr, TRP­1 and Dct, as well as genes for melanosome biogenesis and 37 Chapter II – Medic and Ziman, 2009 melanin stabilisation, such as SILV and Melan­A, begin in unpigmented undifferentiated melanoblasts, where they show perinuclear localisation but become cytoplasmic in fully matured melanocytes [188]. Unpigmented differentiating melanoblasts possess early immature, stage I and II melanosomes containing melanogenic enzymes [189]. Melanogenesis is however, a characteristic of later stage III and IV melanosomes which with maturation take position at the periphery of the cytoplasm [190]. Melanocyte stem cells in the adult skin During embryonic development some melanoblasts will undergo transformation towards quiescent cells and form a population of melanocyte stem cells remaining in the bulge area of the hair follicles of adult mice and humans [48,191]. These quiescent cells are characterised as being Dct‐ and Pax3‐positive [150]. Interestingly, other melanoblast markers expressed during embryogenesis, such as Sox10 and Kit, are not detected in bulge melanocyte stem cells, suggesting different mechanisms act to regulate production and maintenance of embryonal melanoblasts and adult melanocyte stem cells. Pax3, Sox10 and Mitf determine the balance between melanocyte differentiation and maintenance of...
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