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New Perspectives on Melanoma_ The Role of PAX3

Coexpression with its downstream target antiapoptotic

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Unformatted text preview: s and more differentiated melanocytes respectively; similarly perhaps they may dictate more or less differentiated melanoma cells that are more or less metastatic. Intriguingly, MITF does not appear to be regulated by PAX3 in melanoma, since PAX3 DNA‐binding to MITF promoter sequences is relatively less efficient in melanoma cells than in melanocytes [16]. This suggests that in melanocytic transformation, PAX3 is involved in some other aspects of melanoma progression not MITF regulation. 48 Chapter II – Medic and Ziman, 2009 PAX3 and BRAF­regulated pathways in melanoma An additional mechanism by which PAX3 and MITF levels are regulated within the tumour cells as via BRAF mediated pathways. One of the genes most frequently mutated in both naevi and melanomas is the BRAF gene [231‐234]. Activating BRAF mutations direct two downstream regulatory pathways: one stimulates the Brn­2 promoter, increasing its expression which drives Pax3 expression [222]. Interestingly, in a BRN2‐negative melanoma cell line, OCT‐1 levels are high, whereas levels of OCT‐1 are low in a BRN2‐positive melanoma cell line [16]. This may explain the persistent expression of PAX3 commonly observed in melanomas [21,23‐25,73,151]. The second pathways activated by BRAF mutation is MEK‐ERK pathway which leads to decrease MITF levels as a result of degradation of the MITF protein [136,235]. This is evident since in tumours with MITF amplification, often seen together with a BRAF mutation, the actual levels of MITF are not elevated accordingly [136]. Interestingly, oncogenic BRAF exerts control over MITF on two levels. It downregulates the protein by stimulating its degradation, but then counteracts this by increasing transcription through BRN2. Thus oncogenic BRAF plays a critical role in regulating MITF expression resulting in protein levels compatible with proliferation and survival of melanoma cells [236]. Clearly, PAX3 and MITF levels are regulated independently and even synonymously by numerous disregulated pathways in melanoma and together these genes may contribu...
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