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Unformatted text preview: the differentiation program. 41 Chapter II – Medic and Ziman, 2009 PTEN expression is also directly inhibited by Pax3 , at least in myogenesis. PTEN regulates progression through the G1 cell cycle check point, by negatively regulating PI3K/AKT signalling, through cell cycle inhibitor (CDK inhibitor) p27Kip1. Increased expression of Pax3 causes PTEN downregulation and a decrease in apoptosis through the PTEN/AKT pathway, accompanied by downregulation of p27Kip1 . PTEN also directly regulates p53 activity [198,199]. Thus, the apparent antiapoptotic function described for Pax3, a function presumably designed to facilitate migration of undifferentiated cells from the neural crest to the epidermis, may in fact enhance the survival of melanoma cells. Pax3 role in migration Embryonic melanoblast migration is important for movement of cells from the neural crest position to the epidermis. During embryogenesis Pax3 regulates several genes that promote cell migration, including receptor tyrosine kinases; c‐
Ret during enteric ganglia formation [200,201], and cMet during limb muscle and melanocyte development [121,202‐206]. Additionally, Pax3 directly represses expression of NCAM1 [173,207], a cell surface molecule involved in cell‐cell adhesion. Pax3 also activates expression of STX, which causes posttranslational polysialylation of NCAM preventing NCAM‐NCAM‐
mediated homophilic adhesion, leading to decreased cell adhesion and increased migratory properties [204,208]. Other key genes involved in embryonic neural crest migration are TGFα and TGFβ (reviewed in ), both of which are directly regulated by Pax3 [57,58]. TGFβ signalling regulates genes responsible for remodelling the cell‐extracellular matrix and adhesion molecule‐receptors and the cytoskeleton, thus playing a critical role in the regulation of cell‐cell adhesion, growth, differentiation and migration . TGFβ knock‐out mice show neural tube defects , and similarly Pax3‐deficient Splotch...
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