Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1522102 (Melanoma)
 7,698 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germline variants in the melanocortin 1 receptor gene (MC1R) and the p16 gene (CDKN2A) are associated with an increased risk of cutaneous melanoma. The frequency of these germline variants was examined in a population-based, incident series of 62 ocular melanoma cases and ethnicity-matched population controls. In both cases and controls, 59% of individuals carried at least one MC1R variant and there were no significant differences in the frequency of any of the five most common variants of MC1R. We also found no significant differences between cases and controls in the frequency of any of the four most common variants of CDKN2A, and no melanoma case carried a deleterious germline CDKN2A mutation. Our findings argue against an important predisposing effect of the MC1R and CDKN2A genes for ocular melanoma.
Melanoma Res 2003 Aug
PMID:Ocular melanoma is not associated with CDKN2A or MC1R variants--a population-based study. 1288 68

Melanoma is the most devastating form of skin cancer. The steady increase in the incidence of melanoma, its resistance to chemotherapy, together with its high potential to metastasize, have emphasized the importance of its prevention. It is becoming clear that solar ultraviolet radiation is a main culprit in the etiology of melanoma, the same as in basal and squamous cell carcinomas. It is commonly accepted that skin pigmentation and melanin content are principal determinants of the susceptibility to melanoma and other sun-induced skin cancers. Although this is generally true, however, prediction of melanoma risk based solely on pigmentary phenotype is not always precise and fails to identify high-risk individuals with dark skin color. Other important risk factors need to be considered and better defined, particularly DNA repair capacity. Emerging studies have revealed the role of melanoma susceptibility genes in regulating DNA repair, and indicated that melanoma patients have a lower DNA repair capacity than the general population. As the response of human melanocytes to ultraviolet radiation is modulated by an array of paracrine factors, we have focused our investigation on the role of melanocortins and the melanocortin 1 receptor, as well as endothelin-1, in this response. We have discovered novel roles for melanocortins and endothelin-1 as survival factors that rescue human melanocytes from ultraviolet radiation-induced apoptosis, and importantly enhance repair of DNA photoproducts and reduce the release of hydrogen peroxide that can cause oxidative stress. Our findings, together with epidemiological data showing that loss-of-function mutations in the melanocortin-1 receptor gene increase the risk of melanoma, substantiate the role of DNA repair in melanoma genesis, and suggest that responsiveness to melanocortins and endothelin-1 is important for melanoma prevention.
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PMID:Cutaneous photoprotection and melanoma susceptibility: reaching beyond melanin content to the frontiers of DNA repair. 1672 Mar 2

Melanoma is the deadliest form of skin cancer, with no cure for advanced disease. We propose a strategy for melanoma prevention based on using analogs of alpha-melanocyte stimulating hormone (alpha-MSH) that function as melanocortin 1 receptor (MC1R) agonists. Treatment of human melanocytes with alpha-MSH results in stimulation of eumelanin synthesis, reduction of apoptosis that is attributable to reduced hydrogen peroxide generation and enhanced repair of DNA photoproducts. These effects should contribute to genomic stability of human melanocytes, thus preventing their malignant transformation to melanoma. Based on these findings, we synthesized and tested the effects of 3 tetrapeptide alpha-MSH analogs, Ac-His-D-Phe-Arg-Trp-NH2, n-Pentadecanoyl- and 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH2, on cultured human melanocytes. The latter two analogs were more potent than the former, or alpha-MSH, in stimulating the activity of tyrosinase, thus melanogenesis, reducing apoptosis and release of hydrogen peroxide and enhancing repair of DNA photoproducts in melanocytes exposed to UV radiation (UVR). The above analogs are MC1R agonists, as their effects were abrogated by an analog of agouti signaling protein, the physiological MC1R antagonist, and were absent in melanocytes expressing loss-of-function MC1R. Analogs, such as 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH2 with prolonged and reversible effects, can potentially be developed into topical agents to prevent skin photocarcinogenesis, particularly melanoma.
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PMID:Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. 1672 76

Malignant transformation of melanocytes leads to melanoma, the most fatal form of skin cancer. Ultraviolet radiation (UVR)-induced DNA photoproducts play an important role in melanomagenesis. Cutaneous melanin content represents a major photoprotective mechanism against UVR-induced DNA damage, and generally correlates inversely with the risk of skin cancer, including melanoma. Melanoma risk is also determined by susceptibility genes, one of which is the melanocortin 1 receptor (MC1R) gene. Certain MC1R alleles are strongly associated with melanoma. We hereby present experimental evidence for the role of two melanoma risk factors, constitutive pigmentation, as assessed by total melanin, eumelanin and pheomelanin contents, and MC1R genotype and function, in determining the induction and repair of DNA photoproducts in cultured human melanocytes after irradiation with increasing doses of UVR. We found that total melanin and eumelanin contents (MC and EC) correlated inversely with the extent of UVR-induced growth arrest, apoptosis and induction of cyclobutane pyrimidine dimers (CPD), but not with hydrogen peroxide release in melanocytes expressing functional MC1R. In comparison, melanocytes with loss-of-function MC1R, regardless of their MC or EC, sustained more UVR-induced apoptosis and CPD, and exhibited reduced CPD repair. Therefore, MC, mainly EC, and MC1R function are independent determinants of UVR-induced DNA damage in melanocytes.
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PMID:Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes. 1682 49

The production of melanin in the hair and skin is tightly regulated by the melanocortin 1 receptor (MC1R) whose activation is controlled by two secreted ligands, alpha-melanocyte stimulating hormone (alphaMSH) and agouti signal protein (ASP). As melanin is extremely stable, lasting years in biological tissues, the mechanism underlying the relatively rapid decrease in visible pigmentation elicited by ASP is of obvious interest. In this study, the effects of ASP and alphaMSH on the regulation of melanin synthesis and on visible pigmentation were assessed in normal murine melanocytes and were compared with the quick depigmenting effect of the tyrosinase inhibitor, phenylthiourea (PTU). alphaMSH increased pheomelanin levels prior to increasing eumelanin content over 4 days of treatment. Conversely, ASP switched off the pigment synthesis pathway, reducing eu- and pheo-melanin synthesis within 1 day of treatment that was proportional to the decrease in tyrosinase protein level and activity. These results demonstrate that the visible depigmentation of melanocytes induced by ASP does not require the degradation of existing melanin but rather is due to the dilution of existing melanin by melanocyte turnover, which emphasizes the importance of pigment distribution to visible color.
Pigment Cell Melanoma Res 2008 Aug
PMID:Regulation of eumelanin/pheomelanin synthesis and visible pigmentation in melanocytes by ligands of the melanocortin 1 receptor. 1862 31

Germline variation of the melanocortin 1 receptor gene (MC1R) is a risk factor for cutaneous melanoma. Recent studies have indicated that the risk is significantly higher for melanomas with somatic BRAF mutations, suggesting that MC1R variants may have a more specific role than their demonstrated effects on skin and hair pigmentation. To address the possibility that MC1R may act like a tumor suppressor gene by creating a permissive condition for melanocytes with specific somatic mutations to proliferate or survive, we analyzed 103 primary melanomas for somatic MC1R mutations and copy number alterations. This cohort included melanomas from skin with and without chronic sun-induced damage, mucosal membranes, and acral skin (palms, soles, and subungual). We did not find somatic mutations or frequent DNA copy number alterations at the MC1R locus, nor any skewed pattern of copy number alterations that would favor one allele type over the other. In conclusion, our findings indicate that MC1R is not a frequent target of somatic alterations in melanoma.
Pigment Cell Melanoma Res 2008 Oct
PMID:Lack of somatic alterations of MC1R in primary melanoma. 1876 57

Exposure of cultured human melanocytes to ultraviolet radiation (UV) results in DNA damage. In melanoma, UV-signature mutations resulting from unrepaired photoproducts are rare, suggesting the possible involvement of oxidative DNA damage in melanocyte malignant transformation. Here we present data demonstrating immediate dose-dependent generation of hydrogen peroxide in UV-irradiated melanocytes, which correlated directly with a decrease in catalase activity. Pretreatment of melanocytes with alpha-melanocortin (alpha-MSH) reduced the UV-induced generation of 7,8-dihydro-8-oxyguanine (8-oxodG), a major form of oxidative DNA damage. Pretreatment with alpha-MSH also increased the protein levels of catalase and ferritin. The effect of alpha-MSH on 8-oxodG induction was mediated by activation of the melanocortin 1 receptor (MC1R), as it was absent in melanocytes expressing loss-of-function MC1R, and blocked by concomitant treatment with an analog of agouti signaling protein (ASIP), ASIP-YY. This study provides unequivocal evidence for induction of oxidative DNA damage by UV in human melanocytes and reduction of this damage by alpha-MSH. Our data unravel some mechanisms by which alpha-MSH protects melanocytes from oxidative DNA damage, which partially explain the strong association of loss-of-function MC1R with melanoma.
Pigment Cell Melanoma Res 2009 Dec
PMID:alpha-MSH activates immediate defense responses to UV-induced oxidative stress in human melanocytes. 1965 42

The K14-SCF transgenic murine model of variant pigmentation is based on epidermal expression of stem cell factor (SCF) on the C57BL/6J background. In this system, constitutive expression of SCF by epidermal keratinocytes results in retention of melanocytes in the interfollicular basal layer and pigmentation of the epidermis itself. Here, we extend this animal model by developing a compound mutant transgenic amelanotic animal defective at both the melanocortin 1 receptor (Mc1r) and tyrosinase (Tyr) loci. In the presence of K14-Scf, tyrosinase-mutant animals (previously thought incapable of synthesizing melanin) exhibited progressive robust epidermal pigmentation with age in the ears and tails. Furthermore, K14-SCF Tyr(c2j/c2j) animals demonstrated tyrosinase expression and enzymatic activity, suggesting that the c2j Tyr defect can be rescued in part by SCF in the ears and tail. Lastly, UV sensitivity of K14-Scf congenic animals depended mainly on the amount of eumelanin present in the skin. These findings suggest that c-kit signaling can overcome the c2j Tyr mutation in the ears and tails of aging animals and that UV resistance depends on accumulation of epidermal eumelanin.
Pigment Cell Melanoma Res 2009 Dec
PMID:Stem cell factor rescues tyrosinase expression and pigmentation in discreet anatomic locations in albino mice. 1968 81

The pigment-type switching system, which controls whether melanocytes produce black/brown eumelanin or yellow/red pheomelanin, is responsible for many familiar coat coloration patterns in both domestic and wild mammals. In conjunction with the accessory proteins attractin and mahogunin ring finger 1, endogenous agonists and antagonists modulate signaling by the melanocortin 1 receptor to determine pigment type. Mutations in pigment-type switching genes can cause a variety of pleiotropic phenotypes, and these are often similar between mutants at different loci because the proteins encoded by these genes act together as part of conserved molecular pathways that are deployed in multiple biological contexts. When this is the case, pigment-type switching provides a powerful model system for elucidating the shared molecular mechanisms underlying the pigmentary and non-pigmentary phenotypes. This review outlines the current understanding of the pigment-type switching pathway and discusses the opportunities that exist for exploring the molecular basis of pleiotropic phenotypes using this model system.
Pigment Cell Melanoma Res 2010 Aug
PMID:Shades of meaning: the pigment-type switching system as a tool for discovery. 2046 96

Polymorphisms in the melanocortin 1 receptor (MC1R) gene have been associated with increased risks of melanoma, but different approaches to study design, analysis, and reporting have hindered comparisons of findings. We aimed to harmonize the published data by conducting a systematic review and meta-analysis of MC1R variants and thereby estimate relative risks and population attributable fractions (PAFs). We identified 20 analytic studies reporting on 25 populations, which presented quantitative data on melanoma risks associated with any of nine MC1R variants. We separately pooled estimates of risk per person and risk per chromosome using a random effects model. Red hair color (RHC) variants had the highest risk of melanoma [summary odds ratios (OR) 2.44, 95% confidence interval (CI) 1.72-3.45, PAF 16.8% CI 0.119-0.202], but non-RHC variants were also associated with increased risk (summary OR 1.29, 95% CI 1.10-1.51, PAF 7.4% CI 0.030-0.112). The summary risk of melanoma associated with individual variants ranged from OR 2.40 for R142H to 1.18 for V60L, although significant heterogeneity was evident for most variants. PAFs ranged from 0.55% for I155T to 6.28% for R151C. Our findings suggest the nine most common MC1R variants make a sizeable contribution to the burden of melanoma. Melanoma research would be greatly assisted by standardized classifications for MC1R variants and consistent reporting conventions. More compatible and comparable research would allow for more powerful data that could be clinically applied to predict melanoma risk.
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PMID:Melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden. 2112 37


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