New Perspectives on Melanoma_ The Role of PAX3

Twoofthewntproteinsthatarealsoimplicatedinmelanomawnt1

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Unformatted text preview: x and meticulously coordinated network of signalling pathways is involved in the regulation of the fate and function of adult epidermal melanocytes, with some pathway components contributing to more than one regulation pathway (reviewed in [36]). Keratinocytes have a significant effect on melanocyte proliferation as well as on melanogenesis, being the cells that are in a direct contact with the external environment, and thus mediating external environmental 14 Chapter I – Thesis Overview signals to melanocytes. Keratinocytes stimulate melanocytes via secretion of mitogens and melanogens, such as α melanocyte‐stimulating hormone (αMSH), adenocorticotropic hormone (ACTH), basic fibroblast growth factor (FGF), stem cell factor (SCF), and endothelins (ETs) [36]. Melanogenic signals and their receptors (like MSH, ACTH/MC1R (melanocortin 1 receptor), ET/EDNRB (endothelin receptor type B), Wnt (wingless‐type MMTV integration site family)/frizzled family receptor) converge mainly on MITF, increasing its transcription and upregulation of pigmentation‐specific genes, leading to increased melanogenesis. On the other hand mitogenic signals mediated by their membrane‐bound receptors (like SCF/cKit, bFGF/FGFR, HGF (hepatocyte growth factor)/c‐Met (met proto‐oncogene)) activate receptor tyrosine kinases, and initiate a cascade of phosphorylation events involving cytoplasmic mitogen‐ activated protein kinases (MAPK) (reviewed in [36]). Disruption in crucial signalling pathways regulating normal melanocyte function, usually as a result of mutations in key genes involved in these pathways, is strongly linked to melanoma‐genesis (reviewed in [104]). Some of these pathways, relevant to this study, are described below. Activation of MAPK (RAS‐RAF‐MER‐ERK) pathway in melanocytes results in increased proliferation, survival, but also in posttranslational MITF phosphorylation [77]. MITF phosphorylation stabilises the MITF‐p300 transactivation complex, enhancing its transcriptional activity on target genes, further contributing to melano...
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