New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: alling. The TGFβ family of signalling molecules plays a role in regulation of a multitude of cellular processes in both normal and cancer cells, including wound healing, epithelial‐to‐mesenchymal transition (EMT), differentiation, proliferation, and response to the immune system [113‐115]. Binding of one of the three main isoforms of TGFβ (TGFβ1, 2 and 3) to a type I and II TGFβ receptor complex, activates phosphorylation of the intracellular mediators SMAD family members 2 and 3 (SMAD2/3), resulting in their translocation into the nucleus, complexing with Smad4, and transcriptional activation/repression of target genes [116]. TGFβ (both 1 and 2) signalling has been shown to exhibit a repressive effect on both melanocyte differentiation and melanogenesis (via downregulation of MITF and PAX3) and to play a major role in driving immaturity and quiescence of 16 Chapter I – Thesis Overview melanocyte stem cells in the bulge [20,117,118]. But TGFβ also inhibits melanocyte proliferation and induces apoptosis [116,117]. In skin, under normal conditions, secretion of TGFβ by keratinocytes inhibits proliferation of epidermal melanocytes, via PAX3 suppression [20]. UV exposure of skin, however, induces downregulation of TGFβ, followed by PAX3 upregulation, and increased melanocyte proliferation and melanogenesis [20]. Secretion of TGFβ1 by proliferating normal melanocytes is found to be induced by exogenous factors [119,120]. It is interesting that both TGFβ1 and TGFβ2 are upregulated by PAX3 [58,121], and PAX3 itself is repressed by TGFβ1 [20], suggesting a negative feedback mechanism, involving PAX3 and TGFβ, which keeps melanocyte proliferation upon mitogenic stimulation under control [119]. A close functional relationship between TGFβ2 and PAX3 is even more evident since they share some common targets (such are MITF, hairy and enhancer of split 1 (HES1) and SRY (sex determining region Y)­ box 9 (SOX9)), while having opposing effects on their regulation [122,123]. In contrast to normal melanocytes, loss of responsiveness to TGFβ–induced gr...
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