Solar UV light is one of the main culprits in the etiology of skin cancers, and skin pigmentation and melanin content are principal determinants of the susceptibility to melanoma and other sun-induced skin cancers [1, 18-22]. migration to the epidermis and survival is dependent on receptor tyrosine kinase (RTK) c-Kit and its ligand stem cell factor (SCF) within the epidermis [3,4]. Mutations of the c-Kit gene lead to patches of hypopigmentation caused by lack of melanocyte migration, termed [5]. Another important signaling molecule in melanocyte migration and development is usually Wnt5a, which signals via the Frizzled-5 receptor [6]. Overexpression of Wnt5a/Frizzled is found in melanomas and associated with increased cell motility and invasiveness [7,8]. Skin keratinocytes obtain melanin pigment from melanocytes, and keratinocytes provide the necessary microenvironment for melanocyte survival, proliferation, differentiation, and migration via production of ligands that interact with melanocyte receptors [1,9-11]. The epidermal melanin unit denotes the symbiotic relationship between one melanocyte transporting melanin via its dendritic processes to approximately 36 keratinocytes [10]. Melanocytes are located around the basement membrane among basal keratinocytes at ratio of 1 1 melanocyte per 5 basal keratinocytes in hematoxylin and eosinstained histologic sections. This balance is usually maintained through regulated induction of melanocyte division. During childhood as the skin surface expands, throughout adulthood to maintain melanocyte numbers, and in response to exposure to sunlight or skin wounding, melanocytes are stimulated to proliferate at a low rate. Melanocyte proliferation entails uncoupling from keratinocytes, loss of their dendrites, cell division, migration along the basement membrane, then recoupling with keratinocytes to form the epidermal melanin unit. Keratinocytes regulate melanocyte growth and expression of melanocyte cell surface receptors via cell adhesion and growth factors, which include E-cadherin, P-cadherin, and desmoglein that are regulated through growth factors such as hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and endothelin-1 (produced by fibroblasts or keratinocytes). Morphogens such as Notch receptors and their ligands also play a role in maintaining melanocyte function and morphology [12]. Loss of keratinocyte regulation characterizes the development of melanoma and is seen UNC0379 in the down-regulation of E-and P-cadherins, up-regulation of melanocyte-melanocyte and melanocyte cell-fibroblast adhesion molecules such as Mel-CAM and N-cadherin, expression of cell-matrix adhesion molecules such as v3 integrins and increased elaboration of metallo-proteinases [10]. The importance in growth factor signaling in producing the malignant phenotype has been shown in experimental models where increased expression of basic fibroblastic growth factor (bFGF), HGF, SCF, and endothelin-3 coupled with UV radiation produced invasive and in situlike tumors [13,14]. Melanins are polymorphous and multifunctional biopolymers, whose UNC0379 biosynthesis involves a metabolic pathway beginning with the oxidation of tyrosine to L-DOPA, followed by a series of divergent steps that give rise to a brown-black pigment (eumelanin) composed predominantly of indolic UNC0379 models and a yellow to reddish-brown pigment (pheomelanin) using a backbone of benzothiazine models [1,2]. Most of human skin and hair pigmentation involves a combination of these pathways giving rise to mixtures of varying composition [1,2]. The phenotypic expression of this is generally classified according to the clinical Fitzpatrick skin types 1 through 6 and emphasizes the inverse relationship between the degree of pigmentation and solar damage to the skin, including photocarcinogenesis. The functions of melanin pigments include protection from UNC0379 UV light, control of vitamin D3 synthesis, FAA and local thermoregulation [1,15,16]. Melanogenesis is usually under complex regulatory control by multiple brokers interacting via pathways activated by receptor-dependent and -impartial mechanisms, in hormonal, autocrine, paracrine, or intracrine fashion [1]. Because of the multidirectional nature and heterogeneous character of the melanogenesis-modifying brokers, its controlling factors are not organized into simple linear sequences, but they interact instead in a multidimensional network, with extensive functional overlapping with connections arranged both in series and in parallel [1,2]. The most important positive regulator of melanogenesis is the MC1 receptor with UNC0379 its ligands melanocortins and ACTH, whereas among the unfavorable regulators, agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized [1,17]. Solar UV light is one of the main culprits in the etiology of skin cancers, and skin pigmentation and melanin content are principal determinants of the susceptibility to melanoma and other sun-induced skin cancers [1, 18-22]. In general, individuals with fair skin who burn.