New Perspectives on Melanoma_ The Role of PAX3

It is interesting that both tgf1 and tgf2 are

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Unformatted text preview: genesis [105]. Disruption and constitutive activation of this pathway, through activating BRAF (v­raf murine sarcoma viral oncogene homologue B1) or NRAS (neuroblastoma RAS viral oncogene homologue), or cKit mutations is recognised in many melanomas [104,106]. Another signalling pathway important for melanocytes is the canonical Wnt signalling pathway, acting through β‐catenin and LEF‐1/TCF. Wnt proteins bind to receptor complexes, including Frizzled‐3 and co‐receptor LDL Related Proteins (LRP5/6). The most proximal intracellular component in a cascade of activation is 15 Chapter I – Thesis Overview molecular adaptor dishevelled (dsh) which gets recruited to the macromolecular complex containing adenomatous polyposis coli (APC) gene product, axin and glycogene synthase kinase‐3β (GSK‐3β). The formation of the complex blocks the phosphorylation of β‐catenin by GSK‐3β, which would target β‐catenin for proteosome‐mediated degradation [107]. This results in translocation of hypophosphorylated β‐catenin into the nucleus where it cooperates with LEF‐1 on target gene promoters, such as Mitf or Dct, enhancing their transcription, thus driving melanocyte differentiation and melanogenesis [19]. Two of the Wnt proteins that are also implicated in melanoma, Wnt1 and Wnt3a, are found crucial for development of the melanoblast [108]. Wnt1 promotes melanoblast precursor expansion or specification, and Wnt3a promotes differentiation along the melanocytic lineage at the expense of other cell lineages [109]. Both of these Wnt proteins are associated with key melanocytic regulators, Pax3 and Mitf; Wnt1 expression is activated by Pax3 [110], whereas Wnt3a activates Mitf [111]. In adult epidermal melanocytes, inhibition of Wnt signalling by dickkopf homologue 1 (DKK1) secreted from fibroblasts in the dermis, suppresses melanocyte density and differentiation [112]. The opposing signalling pathway to Wnt, in terms of its effect on melanocytes, is TGFβ sign...
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