New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: owing similar numbers of undifferentiated and differentiating PAX3‐ expressing cells, and a small number of PAX3‐negative melanocytes. By contrast, the hair matrix contains much larger numbers of PAX3‐negative mature melanocytes [2]. Thus melanocytes express PAX3 along the full differentiation continuum, with its expression diminishing at the very end, in fully mature melanocytes. These cells at the terminal end of differentiation might be cells close to the end of their life span, and perhaps there is no need for PAX3 at this point since the melanogenic cascade is already operational; or perhaps the loss of PAX3 causes their termination, since loss of PAX3 allow cells to undergo apoptosis [27,28]. Nevertheless, it is obvious that normal epidermal melanocytes show variable differentiation levels, from less differentiated to fully mature cells. 98 Chapter V – General Discussion PAX3­regulated melanocyte differentiation network Networks regulating melanocyte differentiation have been established previously and include the synergistic activity of PAX3 and SOX10 to induce MITF, which then activates the whole cascade of melanogenic targets (refer to the Figure 1.1.3. in literature review). However, another member of the SOX family, SOX9 has also been implicated in melanocyte regulation. SOX9 is commonly expressed in cells of melanocytic lineage, including normal melanocytes, naevi and melanomas [16,279,283,284]. In contrast to SOX10, increased levels of SOX9 are found in differentiating melanocytes, particularly after UVB exposure, playing a role in melanogenesis by upregulating MITF, DCT and TYR [16,279]. By contrast, the transcriptional repressor HES1 promotes stem cell maintenance and prevents premature differentiation [122,123,254]. PAX3 is found to directly regulate both HES1 and SOX9 during neural crest development [122,123], to differentially regulate stem cell maintenance and differentiation [285]. We have looked to see if the same PAX3 ‐ HES1, SOX9 regulationaxis is operational in melanocytes. Indeed ChIP experiments show HES1 and SOX9 promoter occupancy by PAX3, supporting our hypothesi...
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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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