New Perspectives on Melanoma_ The Role of PAX3

Similarly brn2 ablation in melanoma results in

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Unformatted text preview: s [3]. Moreover, we observed PAX3 binding to the DCT promoter, an event shown to direct melanocyte stem cell maintenance [19]. It does seem then that PAX3 is promoting or maintaining a less differentiated melanocyte phenotype via HES1, SOX9 and DCT, shown for the first time here to act together in regulating adult epidermal melanocytes. Interestingly, the well known MITF activation by PAX3, known to drive differentiation seems to be lost in adult epidermal melanocytes; we did not observe PAX3 binding to the MITF promoter in melanocytes in any of our experiments. Similarly Pax3 transfection in murine melanocytes did not result in upregulation of Mitf or upregulation of other melanogenic factors [121]. Therefore, regulation of melanocyte differentiation, more complex than initially proposed, is driven by a network of factors, including transcription factors PAX3, SOX10, SOX9, MITF, and HES1, and downstream effectors TYR, TYRP1, DCT, MLANA, and PMEL. Moreover, several of the components of this network have 99 Chapter V – General Discussion been shown to be affected by two major signalling pathways, Wnt and TGFβ. Canonical Wnt signalling pathway is shown to be essential both during hair cycle and associated melanocyte renewal and melanogenesis, mainly affecting MITF activation thus promoting melanocyte differentiation [19,118,149,150]. On the other hand, TGFβ signalling is required for maintenance of bulge melanocyte stem cells [117]. Moreover, it antagonises MITF function reducing melanosome maturation and pigmentation, but also antagonises Wnt signalling, by upregulating Wnt inhibitors [20,124,125,286,287]. Furthermore, TGFβ also suppresses PAX3 and has the opposite effect on HES1 and SOX9 activation to that of PAX3 [20,122,123]. So, perhaps a feedback loop functions between these two factors to maintain melanocyte plasticity, and confers on cells the ability to switch between less and more differentiated phenotypes, given the bidirectional regulation of TGFβ and PAX3 [20,58,121]. Even though PAX3 maintains cel...
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