New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: nd Dct [75,76]. Notably, binding to the MITF promoter requires both the paired and homeodomain of the Pax3 protein in contrast to the TRP­1 and Dct promoters where only the paired domain is required [76]. Different Pax3 isoforms may mediate these different Pax3 binding activities [53]. As noted above, the role of Pax3 in melanocyte development is far broader than just that of regulation of differentiation. Here we also describe the roles of Pax3 in melanocyte survival, maintenance and migration ‐ roles that could implicate Pax3 in promotion of tumourigenesis and metastasis in melanoma. Antiapoptotic role for Pax3 Mounting evidence supports an antiapoptotic role for Pax3. Several known antiapoptotic factors, such as tumour suppressors p53, PTEN and Bcl‐Xl (see later), are direct downstream targets of Pax3 or mediators of Pax3‐induced survival. During embryogenesis, Pax3 regulates neural tube development via inhibition of p53‐mediated apoptosis, keeping cells alive until the morphogenetic program is completed [55]. A neural tube defect observed in Pax3­deficient Splotch mice is mediated in part by p53‐dependant apoptosis. Pax3 regulation of p53 may be via alteration of protein levels, rather than transcriptional repression, since there are no identifiable Pax3 binding sites in the promoter of the p53 gene [55]. Pax3 has a dual effect on p53: it represses transcription of p53‐dependant genes, BAX and HDM2­P2; and promotes p53 protein degradation [56,195]. p53 exhibits its pro‐apoptotic function by promoting transcription of p21Cip/Waf­1, cyclin‐ dependant kinase inhibitor, and members of the BH3 family of pro‐apoptotic genes (BAX, PUMA and NOXA). In overexpression experiments, Pax3 suppresses p53‐ dependant activation of both BAX and HDM2 promoters, but not that of p21Cip/Waf­1 [56]. In contrast, the Pax3 target, Mitf regulates p21Cip1 expression both directly and indirectly, inducing G1 arrest [196]. Mitf cooperates with the hypophosphorylated form of Rb1, to activate p21Cip1 expression, which contributes to cell cycle exit and activation of...
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