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New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: melanocytic regulators, including Mitf [64,65]. Pax3 is also required for proliferation of committed melanoblasts prior to their entry into the early migration staging area [12]. By contrast, Mitf promotes melanoblast survival during and immediately following migration from the dorsal neural tube to the migration staging area [12]. 6 Chapter I – Thesis Overview Figure 1.1.2. Pax3 expression during embryonic development. Pax3 expression is observed in premigratory and migratory neural crest cells, and developing dermomyotome at E12, and in melanoblasts in developing skin at E13 of murine development (adapted from [66]). It is clear therefore, that during embryonic development of melanocytes, Pax3 functions to specify, maintain and expand progenitor cells during completion of the morphogenic program, thus facilitating their proper migration at key points. The central role of Pax3 in melanocyte differentiation The regulation of differentiation is probably, thus far, the best described role of Pax3 in melanocytes. Pax3 directly binds to the Mitf promoter and, in synergy with Sox10, activates Mitf transcription [64,65,67]. On the other hand, Mitf is the key melanogenic regulator, activating the complete melanogenic cascade, from the melanogenic enzyme‐coding genes (such as Tyr, Tyrp1 and Tyrp2/Dct), to the genes encoding the structural components of melanosomes (such as Pmel (premelanosome protein, also known as PMEL17, gp100, or SILV) and Mlana (melan­A, also known as MART1)) (Figure 1.1.3.A) [68‐71]. Thus by activating Mitf, Pax3 drives the cell along a differentiation pathway. At the same time, however, it competes with Mitf for occupancy of the Dct promoter, repressing its transcription and preventing terminal differentiation (Figure 1.1.3.B). Pax3 binding to the Dct promoter is mediated by the Groucho co‐repressor (Grg4), which physically interacts with both Pax3 and Lef (lymphoid enhancer‐binding factor 1); mutations in the Lef binding site in the Dct promoter abolish Pax3‐mediated repression of Dct [19]. Lef1 also acts synergistically with Mitf...
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