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  Indian J Med Microbiol
 

Figure 1: Schematic summary of the molecular mechanisms involving the formation of nevi, dysplastic nevi and melanoma from a normal melanocyte. In skin, keratinocytes and melanocytes function together as epidermal melanin unit to respond to ultraviolet irradiation, the well-known environmental risk factor for skin cancers. In normal skin, ultraviolet induces p53/proopiomelanocortin signaling pathway activation in keratinocytes to stimulate α-melanocyte-stimulating hormone production, which binding to melanocortin 1 receptor on melanocytes to enhance eumelanin formation (the natural sunscreen) in one way, and to induce tumor suppressor, phosphatase and tensin homologs, which inhibits the PI3k/Akt pathway in the other way. Wild-type BRAF in melanocytes can be activated by binding of kit ligand from ultraviolet-irradiated keratinocytes to receptor c-kit or binding of other growth factors to receptor tyrosine kinase, to promote normal melanocyte growth and proliferation. Therefore, α-melanocyte-stimulating hormone/melanocortin 1 receptor/phosphatase and tensin homologs signaling pathway plays an important role to counteract BRAF/MEK/ERK signaling pathway activation induced melanocyte proliferation to prevent melanoma formation. Once the BRAFV600E mutation occurs (mostly with ultraviolet signature), if p53 is intact, ultraviolet will induce p16 expression which in turn induces melanocyte senescence, that is nevi. If phosphatase and tensin homologs loss or p53 mutated or p16 suppressed, the BRAFV600E mutation induced proliferation will become exaggerated, that is melanoma. If phosphatase and tensin homologs partial loss, BRAFV600E mutated nevi may become dysplastic nevi. Abnormal melanocytes may secret exosome carrying programmed cell death ligand-1, which binding to programmed cell death-1 receptor on T cells to escape immune surveillance. Therefore, BRAFV600E mutation is frequently detected in nevi, the senescence status and also with the potential to develop melanoma, if together with melanocortin 1 receptor deficiency, phosphatase and tensin homologs loss, p53 mutation, or p16 suppression. Immune suppression in endogenous environment may impact a lot on the behavior of nevi, dysplastic nevi or melanoma. CK1α inhibition is an ultraviolet-sparing approach to activate p53/kit ligand/Kit pathway to stimulate eumelanin formation, which may provide a rescue for α-melanocyte-stimulating hormone/melanocortin 1 receptor deficiency associated with pheomelanin formation

Figure 1: Schematic summary of the molecular mechanisms involving the formation of nevi, dysplastic nevi and melanoma from a normal melanocyte. In skin, keratinocytes and melanocytes function together as epidermal melanin unit to respond to ultraviolet irradiation, the well-known environmental risk factor for skin cancers. In normal skin, ultraviolet induces p53/<i>proopiomelanocortin</i> signaling pathway activation in keratinocytes to stimulate α-melanocyte-stimulating hormone production, which binding to melanocortin 1 receptor on melanocytes to enhance eumelanin formation (the natural sunscreen) in one way, and to induce tumor suppressor, phosphatase and tensin homologs, which inhibits the PI3k/Akt pathway in the other way. Wild-type BRAF in melanocytes can be activated by binding of kit ligand from ultraviolet-irradiated keratinocytes to receptor c-kit or binding of other growth factors to receptor tyrosine kinase, to promote normal melanocyte growth and proliferation. Therefore, α-melanocyte-stimulating hormone/melanocortin 1 receptor/phosphatase and tensin homologs signaling pathway plays an important role to counteract BRAF/MEK/ERK signaling pathway activation induced melanocyte proliferation to prevent melanoma formation. Once the BRAF<sup>V600E</sup> mutation occurs (mostly with ultraviolet signature), if p53 is intact, ultraviolet will induce p16 expression which in turn induces melanocyte senescence, that is nevi. If phosphatase and tensin homologs loss or p53 mutated or p16 suppressed, the BRAF<sup>V600E</sup> mutation induced proliferation will become exaggerated, that is melanoma. If phosphatase and tensin homologs partial loss, BRAF<sup>V600E</sup> mutated nevi may become dysplastic nevi. Abnormal melanocytes may secret exosome carrying programmed cell death ligand-1, which binding to programmed cell death-1 receptor on T cells to escape immune surveillance. Therefore, BRAF<sup>V600E</sup> mutation is frequently detected in nevi, the senescence status and also with the potential to develop melanoma, if together with melanocortin 1 receptor deficiency, phosphatase and tensin homologs loss, p53 mutation, or p16 suppression. Immune suppression in endogenous environment may impact a lot on the behavior of nevi, dysplastic nevi or melanoma. CK1α inhibition is an ultraviolet-sparing approach to activate p53/kit ligand/Kit pathway to stimulate eumelanin formation, which may provide a rescue for α-melanocyte-stimulating hormone/melanocortin 1 receptor deficiency associated with pheomelanin formation