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Unformatted text preview: trength in melanoma. By contrast, the low MCAM expression and PAX3 binding in melanocytes are consistent with low levels of PAX3/MCAM co‐expression restricted to melanocytes of the growing hair 88 Chapter IV – Medic, Rizos and Ziman, 2011 follicles of normal skin, whereas epidermal melanocytes show no MCAM expression . These observations highlight the likelihood of PAX3 involvement in melanoma progression to metastasis. The overall higher fold enrichment at all gene sites, observed in melanoma compared to melanocytes, suggests a higher affinity of PAX3 for its targets in melanoma, since there is a similar level of PAX3 expression in both cell types. The increased binding might be due to the upregulation of “appropriate” cofactors in melanoma cells, providing a more favourable environment for PAX3 binding to target genes; or perhaps chromatin changes allow increased binding to targets. PAX3 binding efficiency to genes can also be altered in the presence of competitors (such as MITF) and transcriptional activation affected by cofactors (like SOX10, GRG4, DAXX) or antagonists (TGFβ2) [19,64,123]. For example, we did see here a very high increase of TGFβ2 expression in melanoma cells (180.84‐fold, data not shown). Finally, our results show that PAX3 is a key element in the complex regulating networks defining differentiation in melanocytes and melanoma cells, balancing the cells between a less or more differentiated state, through MITF, DCT and TRP1 [19,64,76], together with transcription factors SOX9 and HES1, as well as the TGFβ signalling pathway. We confirm here that MITF, DCT, SOX9 and HES1 are all direct targets of PAX3. It is evident from our results that regulation of the differentiation status of melanocytes and melanoma cells operates via PAX3‐regulated mechanisms. We see exceptionally strong PAX3 binding to SOX9 and HES1 in melanoma, presumably to maintain the less differentiated phenotype. SOX9 promotes melanocyte differentiation, whereas HES1 maintains a less differentiated phenotype [254,279]. PA...
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This document was uploaded on 03/06/2014 for the course CHEMISTRY 12 at National University of Singapore.
- Spring '14