DNA damage due to oncogene-induced DNA replication stress has been proposed as an important mechanism of senescence [13]. Accordingly, molecules involved in DNA damage signaling have been shown to promote oncogenesis

together with BRAF, for example, the loss of p53 [14]. Most evidence for BRAF cooperation exists for phosphatase and tensin homolog (PTEN). PTEN is a tumor suppressor gene that negatively modulates signal transduction via phosphatidylinositol phosphatase (PIP3, a cytosolic Inhibitors,research,lifescience,medical second messenger). This gene encodes for a lipid protein phosphatase that regulates cell growth and survival. Allelic loss or altered expression of PTEN can be observed in tumors. In melanoma, this lost/modified expression is present in 20%/40% of melanoma tumors, respectively [15, 16]. In a mouse model, it was shown that expression of V600EBRAF in melanocytes leads to benign lesions that do not progress to melanoma. However, when PTEN was silenced, these mice developed metastatic tumors with high penetrance [17]. Regarding the family history of melanoma, Inhibitors,research,lifescience,medical a two-fold risk increase has been reported [18], and it was associated to the 9p12 chromosome [19]. In 1994, the cyclin-dependent kinase N2A (CDKN2A) gene was identified [20], and it is now hold as a high-risk Inhibitors,research,lifescience,medical melanoma locus. The CDKN2A gene encodes for two tumor suppressor proteins, XL184 mw p16INK4a and p14ARF, involved in cell cycle

and apoptosis, respectively. Explicitly, p14ARF directly promotes the degradation of human double minute 2 (MDM2). MDM2 promotes ubiquitinylation and proteasomal Inhibitors,research,lifescience,medical degradation of p53. Accordingly, inactivation of p14ARF leads to increased MDM2 levels leading to increased degradation of p53 [21]. The other product of the CDKN2A locus, p16INK4a, prevents cell cycle progression by binding to CDK4/6 and through a series of

events prevents the release of E2F1 (a transcriptional inducer of S-phase genes) [22]. Mutations of p16IK4a, Inhibitors,research,lifescience,medical and similarly of CDK4 gene [23, 24], can therefore lead to increased cell cycle progression. However, despite the contribution of CDKN2A mutations for oncogenesis, the absolute risk MTMR9 of melanoma in mutation carriers is still highly shaped by environmental and pedigree factors [25]. In close relation to pedigree structure is skin pigmentation; the positive connection between light skin color and melanoma risks is well known. Melanocortin-1 receptor (MC1-R) is responsible for the cutaneous pigmentation, and, interestingly, it has been reported as being overexpressed in both melanotic and amelanotic melanomas [26]. There are two forms of epidermal melanin: eumelanin (with a black-brown color) and pheomelanin (red-yellow color). The synthesis of eumelanin—in charge of UV attenuation—is stimulated by the activation of the MC1-R, through the binding of the tridecapeptide α-MSH, or α-melanocortin stimulating hormone [27–29].