New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: in maintaining committed progenitor cells is similarly observed in other Pax3‐dependant lineages, namely in neuronal [122] and myogenic (reviewed in [15]) lineages. In regulating neuronal precursors, Pax3 plays a dual role: at early stages of development it acts to maintain “stemness” of migratory neural cells, via the repressor Hes1. Later it initiates neuronal lineage specification via the proneural activator Ngn2 [122]. Hes1, is also implicated in maintenance of both embryonic melanoblasts and melanocyte stem cells in the bulge area of adult mouse hair follicles, possibly via Pax3 [194]. The pathways by which Pax3 maintains “stemness” have been detailed for melanocyte stem cells of the bulge area of the adult mouse hair follicle. Pax3 inhibits differentiation by binding to the Dct promoter acting to repress Dct. Grg4 (Groucho co‐repressor) is also required for this interaction; it physically binds both Pax3 and Lef1 to forms a complex on the Dct promoter. Lef1 is also a cofactor for β‐catenin (activated by Wnt signalling), which displaces Grg4 together with Pax3, allowing Mitf to bind to the response element within the Dct promoter. Pax3 has a higher affinity for the Dct promoter, thus replacing Mitf when present at equal or higher concentrations [19]. Mitf binding to Dct and other genes encoding enzymes for melanin synthesis Tyr, TRP­1 initiates the melanogenic cascade. Thus Pax3 acts as a molecular switch to direct this process by binding either to the Dct promoter to inhibit differentiation or to the Mitf promoter in synergy with Sox10 to activate Mitf transcription [64,65,67] and the differentiation pathway. In fact, Pax3 plays an even more complex role in regulation of melanocyte differentiation; Pax3 also has the ability to directly bind to and positively regulate the TRP­1 promoter [73,74] thus enhancing the melanogenic cascade. In summary, Pax3 interacts with distinct recognition motifs found in the promoters of MITF, 40 Chapter II – Medic and Ziman, 2009 TRP­1 a...
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This document was uploaded on 03/06/2014 for the course CHEMISTRY 12 at National University of Singapore.

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