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New Perspectives on Melanoma_ The Role of PAX3

75buddpsjacksonij1995structureofthemousetyrosinaserela

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Unformatted text preview: Two shorter isoforms, PAX3A and B, both lack the homeodomain and the C‐terminus; while the other longer isoforms differ in the structure of the transactivation domain. 109 Chapter VI – Conclusion Different PAX3 transcripts are shown to differentially impact on cellular processes, when transfected into a nontumourigenic murine melanocyte cell line. PAX3C, D and H transcripts for example increase cell transformation, proliferation, migration and survival; whereas PAX3A and B exhibit the opposite effect, and PAX3E and G reduce melanocyte growth and increase apoptosis [163]. Interestingly, PAX3C and PAX3D transcripts are more commonly expressed in melanomas [168], suggesting these isoforms might be driving melanoma progression. It is possible that differences observed between PAX3‐regulated pathways in melanoma and melanocytes could be attributed to different predominant isoforms in each cell type. Therefore, the expression pattern of PAX3 transcripts in melanoma cells lines vs. melanocytes needs to be thoroughly investigated. Another possible determinant of differential PAX3 activity in melanoma is posttranslational modification of the PAX3 protein. Several recent studies have reported that PAX3 protein modifications, such is ubiquitination or acetylation, can switch PAX3 activity from promoting myogenic and neuronal stem cell maintenance to initiating a differentiation program [218,285]. Similarly, changing patterns of Pax3 phosphorylation (at Ser205, 201, and 209) have been seen in proliferating compared to differentiating mouse primary myoblasts [216,335,336]. According to the model proposed by Dietz and colleagues [336], the initial phosphorylation of Ser205 by CK2 in proliferating myoblasts promotes the GSKβ‐ dependant phosphorylation of Ser201, followed by the subsequent dephosphorylation of Ser205. Upon induction of differentiation, phosphorylation at Ser205 is completely abolished, whereas phosphorylation at Ser201 persists, and is accompanied by a rapid increa...
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