Unformatted text preview: X3 represses SOX9, and activates HES1, whereas TGFβ2 has the opposite effect . However, we do not see the expected changes in SOX9 and HES1 expression levels in these cells. One likely explanation is the significant upregulation of TGFβ2 in melanoma, known to antagonise PAX3, which could override PAX3‐regulated SOX9 repression and HES1 activation. 89 Chapter IV – Medic, Rizos and Ziman, 2011 Moreover, we find that NES is regulated by PAX3 exclusively in melanoma cells. NES is thought to mark a subpopulation of quiescent melanoma ‘stem’ cells with higher metastatic potential , which contribute to melanoma progression. It is interesting to note that even though PAX3 is known to activate MITF, and MITF expression in melanocytes is very high, its promoter shows minimal occupancy by PAX3. This suggests limited involvement of PAX3 in transcriptional regulation of MITF in melanocytes. Indeed, melanocyte transfection with Pax3 did not result in an increase in Mitf , confirming that Pax3 is not required to activate Mitf in these cells. It is possible that, in contrast to embryonic development, once the required level of MITF has been established in postnatal melanocytes, PAX3 is no longer necessary for its maintenance. In melanomas, however, PAX3 might once again regulate MITF, maintaining low to intermediate levels required to promote proliferation rather than differentiation . In conclusion, the key transcription factor PAX3 is expressed both in normal melanocytes and melanoma cells and regulates a number of processes similarly in both cells. In melanoma cells however, PAX3 appears to have a higher affinity /binding capacity for target genes, which regulate cell proliferation and cell survival. Since PAX3 acts as an internal rheostat to regulate cell differentiation, and maintenance of the stem cell phenotype, its expression in melanocytes and then in melanoma cells may increase the aggressive phenotype associated with metastatic melanoma, by promoting proliferation and preventing apoptosis, a lethal mixture. Moreover, by conferring migra...
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