BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Melanomas arise from the malignant transformation of melanocytes. Melanocytes are the pigment producing cells of the skin and are derived from neural crest stem cells. Their development is modulated by the receptor tyrosine kinase c-KIT and microphthalmia-associated transcription factor (MITF), two genes that are mutated or amplified in many melanomas .
Melanocytes can produce multiple types of pigment, most obviously dark brown eumelanin and reddish pheomelanin. Pro-pigmentation signaling is initiated by binding of a-melanocyte stimulating hormone (a-MSH) to the melanocortin 1 receptor (MC1R) on the melanocyte cell surface. MC1R is a seven-transmembrane G-protein-coupled receptor that activates adenylate cyclase, leading to increased intracellular cAMP levels and expression of MITF. MITF in turn induces transcription of pigment synthesis genes and production of melanin . Although many loci are involved in human pigmentation, MC1R is a major determinant of pigmentation phenotype. MC1R polymorphisms involving single amino-acid substitutions can reduce MC1R signaling, resulting in impaired eumelanin production and a red hair/ fair skin phenotype .
In addition to basal pigmentation, acquired pigmentation can occur in response to stimuli such as ultraviolet radiation (UVR). Eumelanin is the pigment that provides UVR attenuation in darkly pigmented skin. The tanning response to UVR has been shown to involve p53 activation in keratinocytes following UV-induced DNA damage, leading to p53-mediated POMC/MSH expression. Secreted MSH stimulates MC1R in neighboring melanocytes and produces cutaneous pigmentation .
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