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New Perspectives on Melanoma_ The Role of PAX3

In melanocytes four genomic sites nes tpd52 bcl2l1

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Unformatted text preview: in melanoma cells. By contrast, PAX3‐mediated regulation of melanoma cell proliferation (through TPD52) and survival (via BCL2L1 and PTEN) differs from that in melanocytes. These results suggest that by controlling cell proliferation, survival and migration as well as maintaining a less differentiated “stem” cell like phenotype, PAX3 may contribute to melanoma development and progression. Keywords: PAX3, melanoma, melanocyte 78 Chapter IV – Medic, Rizos and Ziman, 2011 Introduction Melanoma is an aggressive skin cancer and mortality rates remain high for advanced stage patients where the five year survival rate is less that 20% [8]. Current therapies have limited success, and while targeted therapies are proving more successful [30‐32], knowledge of the mechanisms that drive disease progression is urgently required. Of particular interest here are the key regulators of cellular process in both normal skin melanocytes and melanoma cells, as differences between these two are likely to provide strategic clues to the process of melanoma‐genesis. The transcription factor, Paired box 3 (PAX3), is at the top of the hierarchy of genes that regulate melanocyte specification, maintenance of the undifferentiated state, proliferation and migration during embryonic development (reviewed in [1]). PAX3 is also highly expressed in melanoma [24,25], where it is shown to contribute to melanoma cell survival [27,28]; however, it is not known whether it continues to control pathways of differentiation, migration and proliferation and whether this contributes to melanoma progression. In contrast to its well known role in embryonic development and in maintenance of the undifferentiated postnatal melanocyte stem cell [19], not much is known about the role of PAX3 in adult epidermal melanocytes, since its expression there has only recently been confirmed [2,18]. Our own studies indicate that PAX3‐ positive epidermal melanocytes exhibit a variable phenotype, from a more mature to a less differentiated and proliferative form, frequently showing expression of the antiapoptotic factor BCL2 like protein 1 (BCL2L1) [2]. Taken together with other studies [20,163], the resul...
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