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New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: c lesions. We have also identified novel PAX3 targets and mechanisms differentially regulated in 108 Chapter VI – Conclusion melanoma cells, compared to melanocytes. These results add to our knowledge of melanocyte biology, opening a new perspective on PAX3 and its role in melanoma progression. Future directions This study has identified differential and common PAX3 targets in melanocytes and melanoma cells, implicating it in regulation of proliferation, survival and migration, as well as in maintenance of a less differentiated cell state, in both cell types. Further investigation is however required to clarify the precise mechanisms of PAX3 regulation of these processes. We have observed that PAX3 binding to its targets, and presumably its activity, is more prominent in melanoma cells compared to melanocytes; however the exact reasons for this are not known. Neither is it known why some PAX3 targets are different in melanoma cells to those in melanocytes. The main query arising from this study is how does PAX3 employ different mechanisms of action in different cell types? What are the factors that modulate/enhance PAX3 activity in melanoma, and how does that translate into the functional outcome? Further investigation including functional and mechanistic analysis of PAX3 regulation of downstream pathways in melanoma is required to answer these questions. One possible explanation lies in different PAX3 isoforms. By alternative splicing, a single PAX3 gene is able to encode multiple isoforms, that differ in the structure of their paired, homeodomain and/or transactivation domains, and ultimately in binding activity and function [177‐179]. For example, the inclusion of Glutamine (Q) within the linker region between the paired HTH motifs (PAX3Q+ isoform), alters the binding affinity of the paired domain compared to the Q‐ isoform [333,334]. In addition to the Q+ and Q‐ isoforms at least eight more PAX3 isoforms have been reported to date (named as PAX3A‐I) [11,151,168,177]....
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