Kadekaro AL, Leachman S, Kavanagh RJ et alMelanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. FASEB J 24:3850-3860

Department of Dermatology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0592, USA.
The FASEB Journal (Impact Factor: 5.04). 10/2010; 24(10):3850-60. DOI: 10.1096/fj.10-158485
Source: PubMed


The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to α-melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.

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    • "High levels of H 2 O 2 inactivate and reduce the levels of methionine sulfoxide reductase A and B, and thioredoxin/ thioredoxin reductase, thus contributing to oxidative stress and melanocyte death in vitiligo (Schallreuter et al., 2008; Zhou et al., 2009). In addition, high levels of H 2 O 2 in the epidermis are found to oxidize proopiomelanocortin-derived bioactive peptides ACTH and a-MSH, both of which have antioxidant and survival effects on human melanocytes, and this effect can be mitigated by treatment with pseudocatalase (Kadekaro et al., 2005; Spencer et al., 2007; Kadekaro et al., 2010). These findings suggest that the pro-oxidant state of vitiligo skin is causal for melanocyte death. "
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    ABSTRACT: Epidermal melanocytes are particularly vulnerable to oxidative stress owing to the pro-oxidant state generated during melanin synthesis, and to the intrinsic antioxidant defenses that are compromised in pathologic conditions. Melanoma is thought to be oxidative stress driven, and melanocyte death in vitiligo is thought to be instigated by a highly pro-oxidant state in the epidermis. We review the current knowledge about melanin and the redox state of melanocytes, how paracrine factors help counteract oxidative stress, the role of oxidative stress in melanoma initiation and progression and in melanocyte death in vitiligo, and how this knowledge can be harnessed for melanoma and vitiligo treatment.Journal of Investigative Dermatology advance online publication, 27 February 2014; doi:10.1038/jid.2014.65.
    Journal of Investigative Dermatology 02/2014; 134(6). DOI:10.1038/jid.2014.65 · 7.22 Impact Factor
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    • "We have previously reported that exposure to UVR induces both cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimodone photoproducts in WT MC1R melanocytes (MCs) cocultured with keratinocytes (Roberts et al., 2008), consistent with that reported in monoculture experiments (Abdel-Malek et al., 2010; Kadekaro et al., 2010). Others have shown that the repair of cyclobutane pyrimidine dimers is either abrogated or slower in human MCs, with a loss of MC1R function, and the ability to repair DNA damage is independent of the amount of pheomelanin or eumelanin contents and their associated MC1R genotypes (Hauser et al., 2006; Abdel-Malek et al., 2009). "
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    ABSTRACT: Variant alleles of the human melanocortin 1 receptor (MC1R) reduce the ability of melanocytes to produce the dark pigment eumelanin, with R alleles being most deficient. Cultured melanocytes of MC1R R/R variant genotype give reduced responses to [Nle(4), D-Phe(7)]α-melanocyte-stimulating hormone (NDP-MSH) ligand stimulation and lower levels of DNA repair than MC1R wild-type strains. p38 controls xeroderma pigmentosum (XP)-C recruitment to DNA damage sites through regulating ubiquitylation of the DNA damage-binding protein 2 (DDB2) protein, and p53 is implicated in the nuclear excision repair process through its regulation of XP-C and DDB2 protein expression. We report the effects of MC1R ligand treatment and UVR exposure on phosphorylation of p38 and p53, and DDB2 protein expression in MC1R variant strains. Wild-type MC1R melanocyte strains grown together with keratinocytes in coculture, when treated with NDP-MSH and exposed to UVR, gave synergistic activation of p38 and p53 phosphorylation, and were not replicated by R/R variant melanocytes, which have lower basal levels of phosphorylated forms of p38. Minor increases in p38 phosphorylation status in R/R variant melanocyte cocultures could be attributed to the keratinocytes alone. We also found that MC1R wild-type strains regulate DDB2 protein levels through p38, but MC1R R/R variant melanocytes do not. This work confirms the important functional role that the MC1R receptor plays in UVR stress-induced DNA repair.
    Journal of Investigative Dermatology 02/2012; 132(5):1452-61. DOI:10.1038/jid.2011.473 · 7.22 Impact Factor
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    • "The DNA repair gene apex nuclease 1, also known as apurinic endonuclease APEX1), is important in DNA repair responses to reactive oxygen species (ROS) and oxidative DNA base damage (Robinson et al., 2010). Kadekaro et al. (2010) showed that human melanocytes with two red hair color–associated MC1R alleles were resistant to a-melanocortin (a-MSH)-mediated DNA repair. The same group had earlier shown that MC1R activation mediated reduced oxidative DNA damage in melanocytes when exposed to UV radiation (Song et al., 2009). "
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    ABSTRACT: Inherited MC1R variants modulate MITF transcription factor signaling, which in turn affects tumor cell proliferation, apoptosis, and DNA repair. The aim of this BioGenoMEL collaborative study in 10 melanoma cohorts was to test the hypothesis that inherited variants thereby moderate survival expectation. A survival analysis in the largest cohort (Leeds) was carried out adjusting for factors known to impact on survival. The results were then compared with data from nine smaller cohorts. The absence of any consensus MC1R alleles was associated with a significantly lower risk of death in the Leeds set (HR, 0.64; 95% CI, 0.46-0.89) and overall in the 10 data sets (HR, 0.78; 95% CI, 0.65-0.94) with some support from the nine smaller data sets considered together (HR, 0.83; 95% CI, 0.67-1.04). The data are suggestive of a survival benefit for inherited MC1R variants in melanoma patients.
    Pigment Cell & Melanoma Research 02/2012; 25(3):384-94. DOI:10.1111/j.1755-148X.2012.00982.x · 4.62 Impact Factor
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