New Perspectives on Melanoma_ The Role of PAX3

In vitro experiments show brn2 protein levels and

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Unformatted text preview: mice show diminished levels of TGFβ and neural tube defects. Pax3 binds to a cis‐regulatory element within the TGFβ promoter region, directly regulating its transcription [58]. 42 Chapter II – Medic and Ziman, 2009 Migration of melanoblasts is an important step in melanocyte development and Pax3 appears to facilitate this process. Presumably, Pax3 is also important for the movement of developing melanocytes form the bulge area to the matrix along the hair shaft and into the epidermis. Moreover, migration and dissemination of melanoma cells, a key factor in metastasis may indeed be PAX3 dependent. Pax3 function in differentiated melanocytes The wide spectrum of Pax3 functions performed at given points along the developmental pathway may be operational in adult melanocytes and may in fact continue in melanoma. Alternatively, Pax3 functions associated with embryonic melanocyte genesis may differ from those of adult cells and melanoma cells, or perhaps only a select few functions are activated in each of these cell types. In melanocytes, Pax3 probably functions together with Sox10 in maintenance of upregulation of Mitf and its downstream melanogenic genes to continually produce melanin. Its role in maintenance of differentiated melanocytes remains to be determined. A key question that remains then is how are Pax3 functions regulated temporally? Pax3 accomplishes specific temporal functions via interactions with several specific cofactors present in a particular cell at any given stage of melanocyte development [52,210]. Since Pax3 may have both activating and repressing roles in transcriptional regulation [53,211], it might be that at one point in development it is responsible for repressing and at another moment activating differentiation processes, mediating and coordinating the cell fate in response to environmental cues [52]. Changes in binding affinity and efficiency to downstream targets are important determinants of Pax3 functional activity. In fact, in melanoblasts it preferentially binds to the...
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