Humanmelanocortin 1 receptorvariants, receptor function and melanocyte response to UV radiation

Abstract

Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin synthesized by epidermal melanocytes and is known to protect against sun-induced DNA damage. The synthesis of eumelanin is stimulated by the binding of α-melanotropin (α-melanocyte-stimulating hormone)to the functional melanocortin 1 receptor (MC1R) expressed on melanocytes. The human MC1R gene is highly polymorphic and certain allelic variants of the gene are associated with red hair phenotype, melanoma and non-melanoma skin cancer. The importance of the MC1R gene in determining skin cancer risk led us to examine the impact of specific polymorphisms in this gene on the responses of human melanocytes to α-melanotropin and UV radiation. We compared the ability of human melanocyte cultures, each derived from a single donor, to respond to α-melanotropin with dose-dependent stimulation of cAMP formation, tyrosinase activity and proliferation. In each of those cultures the MC1R gene was sequenced, and the eumelanin and pheomelanin contents were determined. Human melanocytes homozygous for Arg160Trp, heterozygous for Arg160Trp and Asp294His, or for Arg151Cys and Asp294His substitutions, but not melanocytes homozygous for Val92Met substitution, in the MC1R demonstrated a significantly reduced response toα-melanotropin. Additionally, melanocytes with a non-functional MC1R demonstrated a pronounced increase in their sensitivity to the cytotoxic effect of UV radiation compared with melanocytes expressing functional MC1R. We conclude that loss-of-function mutations in the MC1R gene sensitize human melanocytes to the DNA damaging effects of UV radiation, which may increase skin cancer risk.

Cell surface expression of melanocortin-1 receptor on HaCaT keratinocytes and α-melanocortin stimulation do not affect the formation and repair of UVB-induced DNA photoproducts

“…4, 5 Furthermore, loss-of-function mutations in the MC1R gene sensitizes human melanocytes to the DNA damaging effects of UV radiation, which may increase skin cancer risk. 6 Recent data indicate that the risk for MM associated with MC1R is due to an increase in risk of developing MM with mutations of the BRAF oncogene. 7 Normal human keratinocytes produce very low levels of a-MSH that can be enhanced by UV exposure to a much greater extent than in melanocytes.…”

Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma

“…MC1R is inactivated in people with red hair, due to polymorphism(s) that make(s) them more susceptible to melanoma than dark-skinned individuals. For example, variants of the gene encoding MC1R, mainly R151C, R160W, and D294H, have been shown to be associated with light and poorly pigmented skin [55], whereas the WT form is associated with dark, highly pigmented skin [56,57]. Similarly, patients with mutations in proopiomelanocortin (POMC) genes-encoding the precursor of αMSH-have red hair [58] These variants decrease the sensitivity of the receptor and binding of the hormone α-MSH, produced by keratinocytes in response to UVR.…”

Behind the Scene: Exploiting MC1R in Skin Cancer Risk and Prevention

“…Interestingly, paracrine factors produced by keratinocytes such as endothelin 1 (EDN1) and basic fibroblast growth factor (bFGF), act through their corresponding receptors on the plasma membrane of melanocytes to increase proliferation and differentiation. EDN1 mediates a dose-dependent upregulation of MC1R mRNA in normal human melanocytes [28], while the effects of bFGF are less clear, although an upregulation has been reported [28]. Interleukin-1-α (IL-1α) and interleukin-1-β (IL-1β) upregulate MC1R mRNA in normal human melanocytes [23], while TNF-α [29] and TGF-β [30], that potently repress melanogenesis in melanoma cells, moderately downregulate MC1R expression in normal melanocytes [23] and mouse melanoma cells [31].…”

“…There is also evidence for a heterozygote effect on beard hair color, skin type and freckling [128], although an association between MC1R RHC polymorphisms and freckles has been demonstrated to be independent of skin and hair color [131]. A dosage effect of MC1R variant alleles on sensitivity to UVR has also been described [28]. Accordingly, heterozygotes for one variant allele show an intermediate ability to tan after repeated sun exposure between those with two variant alleles (most likely to be red hair subjects) and those with none of the variants.…”

“…Genome-wide association studies (GWAS) and meta-analyses have widely demonstrated the association of RHC variants with increased risk of melanoma [124,[138][139][140][141] and NMSCs [71,124,131,142,143]. These associations were initially related to the pigmentary functions of MC1R, although many studies confirmed that the increased skin cancer susceptibility in MC1R carriers is independent from pigmentary traits [28,71,[144][145][146].…”