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New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: to activate the Dct promoter [72]. In 7 Chapter I – Thesis Overview the presence of nuclear β‐catenin, however, Grg4, and hence Pax3, are displaced from the Dct promoter, allowing Mitf to bind to the response element within the Dct promoter (common to both Pax3 and Mitf), initiating its transcription (Figure 1.1.3.C) [19]. Figure 1.1.3. Schematic representation of regulation of melanogenic gene expression. A) Pax3 activates a cascade of melanocytic gene expression. B) Pax3 activates Mitf (in synergy with Sox10) and represses Dct transcription at the same time. Wnt signalling abolishes Pax3 mediated repression of Dct. C) Pax3 binding to the Dct promoter is mediated by formation of a Groucho/ Lef/Tcf complex while β‐catenin, activated by Wnt signalling, can displace Pax3 from the complex (Adapted from [19]) Pax3 also directly binds to the promoter region of the melanogenic enzyme, Tyrp1 [73,74]. Pax3 can therefore regulate melanocyte differentiation both indirectly, through Mitf, or directly by regulating Tyrp1 and Dct [75,76]. It is not certain however whether these mechanisms act at all stages of melanocytic development, or whether the latter mechanism is a common regulatory mechanism at all. Nevertheless, it is clear that Pax3 determines melanocytic cell fate while keeping the cell in an undifferentiated state, poised to differentiate in response to external stimuli [52]. It is likely that Pax3 prevents premature differentiation of melanoblasts during their migration, while contributing to their proliferation and expansion. Less clear is the function of Pax3 in melanocytes once they reach the skin. 8 Chapter I – Thesis Overview 1.2. Melanocytes of the adult skin Human skin melanocytes are located both in the hair follicles and at the epidermal‐ dermal boundary (Figure 1.1.4.). Interfollicular/ epidermal melanocytes are lodged between basal cells, and form close relationships with epidermal keratinocytes, to which they distribute melanin, giving skin its pigmentation. Follicular melanocytes are located in the bulb of the hair follicle where they contribute to pigmentation of the growing hair. These two melanocyte populations are predominantly mature differentiated pigment‐producing...
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