New Perspectives on Melanoma_ The Role of PAX3

Bycontrollingthecrucialcellularprocessessuchasprolifer

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Unformatted text preview: ls in a less differentiated state, it remains expressed even in cells that are undergoing differentiation, hence we see its co‐ expression with markers of differentiated melanocytes, like MLANA. It is likely to regulate other cellular processes at this point, like proliferation, survival or migration. It is possible therefore that a loss of PAX3 in terminally differentiated mature melanocytes might signal their terminal end point, and apoptosis. Significance of PAX3 expression in normal melanocytes Several studies, undoubtedly show an antiapoptotic role for PAX3 [27,28], suggesting regulation of BCL2L1, p53 and PTEN as mediators of this action [28,55,197,226]. Here we looked at BCL2L1 and PTEN as potential targets of PAX3 in melanocytes and melanoma cells. We observe co‐expression of PAX3 and BCL2L1 in a similar proportion of cells in normal melanocytes, naevi and primary melanomas. No co‐ expression was observed in metastatic melanoma samples, where in fact only one sample was positive for BCL2L1 [2]. These results do suggest PAX3‐mediated survival via BCL2L1. However, ChIP experiments show no PAX3 binding to BCL2L1 100 Chapter V – General Discussion at all in melanocytes, and low binding in a metastatic melanoma cell line [3]. Taken together, these results could mean that PAX3 acts as a transcriptional repressor of BCL2L1, and because it does not bind in melanocytes, both PAX3 and BCL2L1 do co‐express in the same cell, whereas in metastatic melanoma cells PAX3 binds to BCL2L1, preventing transcription, therefore co‐expression is not observed; lower levels of BCL2L1 mRNA observed in melanoma cells, by RT‐qPCR, support this view. Alternatively, PAX3 does activate BCL2L1 (as others have suggested), and we see co‐expression in most of our samples, but the promoter region we have chosen for ChIP experiments might not be correct. Another explanation might lie in alternative BCL2L1 isoforms shown to have different biological functions; the longer isoform 1 (also known as Bcl‐xl) is antiapoptotic,...
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