New Perspectives on Melanoma_ The Role of PAX3

Pax3 is known to directly regulate tgf 58 whereas

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Unformatted text preview: to date phosphorylated Pax3 has only been seen in proliferating mouse primary myoblasts [216,217]. Pax3 protein stability is regulated by ubiquitination and proteasomal degradation during adult muscle stem cell activation [218]. 44 Chapter II – Medic and Ziman, 2009 Function determined by Pax3 levels It is not certain how Pax3 protein levels determine its function(s). In neural crest cells that are Pax3‐ and Sox10‐positive but Mitf‐negative, Pax3 expands the pool of undifferentiated cells. Pax3 protein concentration (together with Sox10) may need to reach a certain threshold in order to activate Mitf transcription and commit cells to melanogenic lineage [73]. Indeed the amount of Pax3 protein appears to be a key factor in determining its role in neural crest determination in developing Xenopus embryos where different levels of Pax3 are required for activation of different downstream targets. Intermediate doses induce Snail2 expression and neural crest formation, and in high doses Pax3 strongly induces Xhe, thus changing the cell fate towards that of a hatching gland cell [219]. Once Mitf is activated in melanoblasts it is possible that Pax3 function may be driven, to some extent, by relative Mitf levels; Mitf needs to exceed a certain threshold, much higher that the amount of Pax3, in order to drive the differentiation pathway. In vitro experiments suggest that once the level of Mitf reaches an amount significantly greater than that of Pax3 [19] repression of differentiation is no longer possible and the melanogenic cascade is initiated. Factors that upregulate Pax3 may also provide a clue as to its temporal functions. Transcription factors N­Myc and c­Myc are both regulators of Pax3 transcription [220]. Myc is actively transcribed in proliferating cells but very little is found in senescent or differentiated cells. The cell cycle oscillation of Myc and Pax3 mRNA levels was studied in cells in vitro; both are undetectable during starvation‐ induced growth arrest, but increase after addition of medium, yet decrease again...
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