Protection against UVR Involves MC1R-Mediated Non-Pigmentary and Pigmentary Mechanisms In Vivo

Abstract

Individuals with red hair and fair skin due to MC1R gene variants are at higher risk of cutaneous neoplasia, consistent with MC1R having a role in photoprotection. The exact reasons for greater UVR susceptibility as a result of compromised MC1R function are unclear, but hypotheses include reduced photoprotection due to less eumelanin, pheomelanin-induced phototoxicity, and lower protection by "non-pigmentary" MC1R effects. To determine how MC1R photoprotects, an in vivo hairless MC1R model containing Mc1r(-/-) albino, MC1R(+)Mc1r(-/-) albino, Mc1r(-/-) pigmented, and MC1R(+)Mc1r(-/-) pigmented mice was generated. After single doses of UVR, no significant differences in epidermal cyclobutane pyrimidine dimers or sunburn cell (SBC) formation were observed between pigmented and albino groups. However, after repeated UVR exposure, the number of p53 clones in albino skin was significantly elevated when this was null for MC1R. Furthermore, in the absence of functional MC1R, fewer p53 clones were observed in pigmented than in albino skin. The results indicate that MC1R protects by a combination of pigmentary and non-pigmentary effects in vivo and that when MC1R function is compromised the melanin type in skin is still protective against UVR.

Germline melanoma susceptibility and prognostic genes: A review of the literature

“…41,[49][50][51][52] The higher pheomelanin levels associated with these MC1R variant alleles cause the red hair and fair skin phenotype (red hair color [RHC]), also known as the MC1R null phenotype. 53 This subpopulation is known to be more sensitive to the effects of UV irradiation, demonstrated by a lack of tanning ability, and is also at increased risk of developing CMM, by mechanisms yet to be fully understood.…”

Melanoma: Advances in Targeted Therapy and Molecular Markers

“…2 To date, the most important germ-line mutations identified in melanoma include CDK2NA, CDK4, RB1, MC1R, and MITF (Table 1). [3][4][5] Approximately 5-10 % of melanoma is thought to develop Acknowledgement This educational review series, ''Genomic Markers in the Multidisciplinary Treatment of Cancer'' is supported by an independent educational grant from Genomic Health, Inc. The Society of Surgical Oncology offers CME/MOC for this educational review series.…”

La genètica de la pigmentació humana i de la predisposició al càncer de pell

“…Algunes d'aquestes mutacions afecten el risc de càncer de pell, via alteracions en la pigmentació, i també per la seua influència en altres processos (Robinson i altres, 2010). Anàlisis funcionals mostren que variacions en MC1R limiten l'estimulació de la via de pigmentació a causa d'una incompleta unió entre el receptor i el seu lligand (α-MSH), d'això resulta un descens de l'activitat de l'enzim tirosinasa i en la síntesi de feomelanina, la qual és responsable del fenotip de pell clara i cabell roig (Beaumont i altres, 2005).…”