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MC1R Functions, Expression, and Implications for Targeted Therapy

  • Stefania Guida
    Correspondence
    Correspondence: Stefania Guida, Dermatology Unit, Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo, 71, Modena 41125, Italy.
    Affiliations
    Dermatology Unit, Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
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  • Gabriella Guida
    Affiliations
    Molecular Biology Section, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy
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  • Colin Ronald Goding
    Affiliations
    Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
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Published:August 04, 2021DOI:https://doi.org/10.1016/j.jid.2021.06.018
      The G protein-coupled MC1R is expressed in melanocytes and has a pivotal role in human skin pigmentation, with reduced function in human genetic variants exhibiting a red hair phenotype and increased melanoma predisposition. Beyond its role in pigmentation, MC1R is increasingly recognized as promoting UV-induced DNA damage repair. Consequently, there is mounting interest in targeting MC1R for therapeutic benefit. However, whether MC1R expression is restricted to melanocytes or is more widely expressed remains a matter of debate. In this paper, we review MC1R function and highlight that unbiased analysis suggests that its expression is restricted to melanocytes, granulocytes, and the brain.

      Abbreviations:

      α-MSH (α–melanocyte-stimulating hormone), Akt (protein kinase B), APT2 (acyl-protein thioesterase 2), C315 (cysteine 315), EPP (erythropoietic protoporphyria), ERK (extracellular signal‒regulated kinase), GPCR (G protein-coupled receptor), HEK (human embryonic kidney), KC (keratinocyte), LOF (loss of function), MMP (matrix metalloprotease), NER (nucleotide excision repair), PI3K (phosphatidylinositol 3-kinase), RHC (red hair color), WT (wild type)
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      References

        • Abdel-Malek Z.
        • Scott M.C.
        • Suzuki I.
        • Tada A.
        • Im S.
        • Lamoreux L.
        • et al.
        The melanocortin-1 receptor is a key regulator of human cutaneous pigmentation.
        Pigment Cell Res. 2000; 13: 156-162
        • Abdel-Malek Z.
        • Suzuki I.
        • Tada A.
        • Im S.
        • Akcali C.
        The melanocortin-1 receptor and human pigmentation.
        Ann N Y Acad Sci. 1999; 885: 117-133
        • Abdel-Malek Z.A.
        • Swope V.B.
        • Starner R.J.
        • Koikov L.
        • Cassidy P.
        • Leachman S.
        Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention.
        Arch Biochem Biophys. 2014; 563: 4-12
        • Almeida Scalvino S.
        • Chapelle A.
        • Hajem N.
        • Lati E.
        • Gasser P.
        • Choulot J.C.
        • et al.
        Efficacy of an agonist of α-MSH, the palmitoyl tetrapeptide-20, in hair pigmentation.
        Int J Cosmet Sci. 2018; 40: 516-524
        • April C.S.
        • Barsh G.S.
        Distinct pigmentary and melanocortin 1 receptor-dependent components of cutaneous defense against ultraviolet radiation.
        PLoS Genet. 2007; 3: e9
        • Bautista R.M.
        • Carter K.M.
        • Jarrett S.G.
        • Napier D.
        • Wakamatsu K.
        • Ito S.
        • et al.
        Cutaneous pharmacologic cAMP induction induces melanization of the skin and improves recovery from ultraviolet injury in melanocortin 1 receptor-intact or heterozygous skin.
        Pigment Cell Melanoma Res. 2020; 33: 30-40
        • Beaumont K.A.
        • Newton R.A.
        • Smit D.J.
        • Leonard J.H.
        • Stow J.L.
        • Sturm R.A.
        Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk.
        Hum Mol Genet. 2005; 14: 2145-2154
        • Beaumont K.A.
        • Shekar S.N.
        • Cook A.L.
        • Duffy D.L.
        • Sturm R.A.
        Red hair is the null phenotype of MC1R.
        Hum Mutat. 2008; 29: E88-E94
        • Beaumont K.A.
        • Shekar S.N.
        • Newton R.A.
        • James M.R.
        • Stow J.L.
        • Duffy D.L.
        • et al.
        Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles [published correction appears in Hum Mol Genet 2007;16:2988].
        Hum Mol Genet. 2007; 16: 2249-2260
        • Bertolotto C.
        • Abbe P.
        • Hemesath T.J.
        • Bille K.
        • Fisher D.E.
        • Ortonne J.P.
        • et al.
        Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes.
        J Cell Biol. 1998; 142: 827-835
        • Böhm M.
        • Stegemann A.
        Bleomycin-induced fibrosis in MC1 signalling-deficient C57BL/6J-Mc1r(e/e) mice further supports a modulating role for melanocortins in collagen synthesis of the skin.
        Exp Dermatol. 2014; 23: 431-433
        • Box N.F.
        • Wyeth J.R.
        • O’Gorman L.E.
        • Martin N.G.
        • Sturm R.A.
        Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair.
        Hum Mol Genet. 1997; 6: 1891-1897
        • Caini S.
        • Gandini S.
        • Botta F.
        • Tagliabue E.
        • Raimondi S.
        • Nagore E.
        • et al.
        MC1R variants and cutaneous melanoma risk according to histological type, body site, and Breslow thickness: a pooled analysis from the M-SKIP project.
        Melanoma Res. 2020; 30: 500-510
        • Cao J.
        • Wan L.
        • Hacker E.
        • Dai X.
        • Lenna S.
        • Jimenez-Cervantes C.
        • et al.
        MC1R is a potent regulator of PTEN after UV exposure in melanocytes.
        Mol Cell. 2013; 51: 409-422
        • Carreira S.
        • Goodall J.
        • Aksan I.
        • La Rocca S.A.
        • Galibert M.D.
        • Denat L.
        • et al.
        Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression.
        Nature. 2005; 433: 764-769
        • Carreira S.
        • Goodall J.
        • Denat L.
        • Rodriguez M.
        • Nuciforo P.
        • Hoek K.S.
        • et al.
        Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.
        Genes Dev. 2006; 20: 3426-3439
        • Cassidy P.B.
        • Abdel-Malek Z.A.
        • Leachman S.A.
        Beyond red hair and sunburns: uncovering the molecular mechanisms of MC1R signaling and repair of UV-induced DNA damage.
        J Invest Dermatol. 2015; 135: 2918-2921
        • Castejón-Griñán M.
        • Herraiz C.
        • Olivares C.
        • Jiménez-Cervantes C.
        • García-Borrón J.C.
        cAMP-independent non-pigmentary actions of variant melanocortin 1 receptor: AKT-mediated activation of protective responses to oxidative DNA damage.
        Oncogene. 2018; 37: 3631-3646
        • Chen S.
        • Han C.
        • Miao X.
        • Li X.
        • Yin C.
        • Zou J.
        • et al.
        Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads.
        Nat Commun. 2019; 10: 877
        • Chen S.
        • Zhu B.
        • Yin C.
        • Liu W.
        • Han C.
        • Chen B.
        • et al.
        Palmitoylation-dependent activation of MC1R prevents melanomagenesis.
        Nature. 2017; 549: 399-403
        • Cheng L.B.
        • Cheng L.
        • Bi H.E.
        • Zhang Z.Q.
        • Yao J.
        • Zhou X.Z.
        • et al.
        Alpha-melanocyte stimulating hormone protects retinal pigment epithelium cells from oxidative stress through activation of melanocortin 1 receptor-Akt-mTOR signaling.
        Biochem Biophys Res Commun. 2014; 443: 447-452
        • Chhajlani V.
        • Wikberg J.E.
        Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA [published correction appears in FEBS Lett 1996;390:238].
        FEBS Lett. 1992; 309: 417-420
        • Cui R.
        • Widlund H.R.
        • Feige E.
        • Lin J.Y.
        • Wilensky D.L.
        • Igras V.E.
        • et al.
        Central role of p53 in the suntan response and pathologic hyperpigmentation.
        Cell. 2007; 128: 853-864
        • Dalziel M.
        • Kolesnichenko M.
        • das Neves R.P.
        • Iborra F.
        • Goding C.
        • Furger A.
        Alpha-MSH regulates intergenic splicing of MC1R and TUBB3 in human melanocytes.
        Nucleic Acids Res. 2011; 39: 2378-2392
        • d’Ischia M.
        • Wakamatsu K.
        • Cicoira F.
        • Di Mauro E.
        • García-Borrón J.C.
        • Commo S.
        • et al.
        Melanins and melanogenesis: from pigment cells to human health and technological applications.
        Pigment Cell Melanoma Res. 2015; 28: 520-544
        • D'Orazio J.A.
        • Nobuhisa T.
        • Cui R.
        • Arya M.
        • Spry M.
        • Wakamatsu K.
        • et al.
        Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning.
        Nature. 2006; 443: 340-344
        • Drouin J.
        • Goodman H.M.
        Most of the coding region of rat ACTH beta--LPH precursor gene lacks intervening sequences.
        Nature. 1980; 288: 610-613
        • Duffy D.L.
        • Box N.F.
        • Chen W.
        • Palmer J.S.
        • Montgomery G.W.
        • James M.R.
        • et al.
        Interactive effects of MC1R and OCA2 on melanoma risk phenotypes.
        Hum Mol Genet. 2004; 13: 447-461
        • Elfakir A.
        • Ezzedine K.
        • Latreille J.
        • Ambroisine L.
        • Jdid R.
        • Galan P.
        • et al.
        Functional MC1R-gene variants are associated with increased risk for severe photoaging of facial skin.
        J Invest Dermatol. 2010; 130: 1107-1115
        • Ferretta A.
        • Maida I.
        • Guida S.
        • Azzariti A.
        • Porcelli L.
        • Tommasi S.
        • et al.
        New insight into the role of metabolic reprogramming in melanoma cells harboring BRAF mutations.
        Biochim Biophys Acta. 2016; 1863: 2710-2718
        • Frändberg P.A.
        • Doufexis M.
        • Kapas S.
        • Chhájlani V.
        Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor.
        Biochem Biophys Res Commun. 1998; 245: 490-492
        • García-Borrón J.C.
        • Abdel-Malek Z.
        • Jiménez-Cervantes C.
        MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation.
        Pigment Cell Melanoma Res. 2014; 27: 699-720
        • García-Borrón J.C.
        • Sánchez-Laorden B.L.
        • Jiménez-Cervantes C.
        Melanocortin-1 receptor structure and functional regulation.
        Pigment Cell Res. 2005; 18: 393-410
        • Giuliano S.
        • Cheli Y.
        • Ohanna M.
        • Bonet C.
        • Beuret L.
        • Bille K.
        • et al.
        Microphthalmia-associated transcription factor controls the DNA damage response and a lineage-specific senescence program in melanomas.
        Cancer Res. 2010; 70: 3813-3822
        • Goding C.R.
        • Arnheiter H.
        MITF-the first 25 years.
        Genes Dev. 2019; 33: 983-1007
        • Guida S.
        • Bartolomeo N.
        • Zanna P.T.
        • Grieco C.
        • Maida I.
        • De Summa S.
        • et al.
        Sporadic melanoma in South-Eastern Italy: the impact of melanocortin 1 receptor (MC1R) polymorphism analysis in low-risk people and report of three novel variants.
        Arch Dermatol Res. 2015; 307: 495-503
        • Guida S.
        • Ciardo S.
        • De Pace B.
        • De Carvalho N.
        • Farnetani F.
        • Pezzini C.
        • et al.
        Atrophic and hypertrophic skin photoaging and melanocortin-1 receptor (MC1R): the missing link.
        J Am Acad Dermatol. 2021; 84: 187-190
        • Guida S.
        • Ciardo S.
        • De Pace B.
        • De Carvalho N.
        • Peccerillo F.
        • Manfredini M.
        • et al.
        The influence of MC1R on dermal morphological features of photo-exposed skin in women revealed by reflectance confocal microscopy and optical coherence tomography.
        Exp Dermatol. 2019; 28: 1321-1327
        • Haq R.
        • Shoag J.
        • Andreu-Perez P.
        • Yokoyama S.
        • Edelman H.
        • Rowe G.C.
        • et al.
        Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF.
        Cancer Cell. 2013; 23: 302-315
        • Harding R.M.
        • Healy E.
        • Ray A.J.
        • Ellis N.S.
        • Flanagan N.
        • Todd C.
        • et al.
        Evidence for variable selective pressures at MC1R.
        Am J Hum Genet. 2000; 66: 1351-1361
        • Hauser J.E.
        • Kadekaro A.L.
        • Kavanagh R.J.
        • Wakamatsu K.
        • Terzieva S.
        • Schwemberger S.
        • et al.
        Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes.
        Pigment Cell Res. 2006; 19: 303-314
        • Herraiz C.
        • Garcia-Borron J.C.
        • Jiménez-Cervantes C.
        • Olivares C.
        MC1R signaling. Intracellular partners and pathophysiological implications.
        Biochim Biophys Acta Mol Basis Dis. 2017; 1863: 2448-2461
        • Herraiz C.
        • Jiménez-Cervantes C.
        • Zanna P.
        • García-Borrón J.C.
        Melanocortin 1 receptor mutations impact differentially on signalling to the cAMP and the ERK mitogen-activated protein kinase pathways.
        FEBS Lett. 2009; 583: 3269-3274
        • Herraiz C.
        • Journé F.
        • Abdel-Malek Z.
        • Ghanem G.
        • Jiménez-Cervantes C.
        • García-Borrón J.C.
        Signaling from the human melanocortin 1 receptor to ERK1 and ERK2 mitogen-activated protein kinases involves transactivation of cKIT.
        Mol Endocrinol. 2011; 25: 138-156
        • Herraiz C.
        • Olivares C.
        • Castejón-Griñán M.
        • Abrisqueta M.
        • Jiménez-Cervantes C.
        • García-Borrón J.C.
        Functional characterization of MC1R-TUBB3 intergenic splice variants of the human melanocortin 1 receptor.
        PLoS One. 2015; 10e0144757
        • Herraiz C.
        • Sánchez-Laorden B.L.
        • Jiménez-Cervantes C.
        • García-Borrón J.C.
        N-glycosylation of the human melanocortin 1 receptor: occupancy of glycosylation sequons and functional role.
        Pigment Cell Melanoma Res. 2011; 24: 479-489
        • Hill R.P.
        • MacNeil S.
        • Haycock J.W.
        Melanocyte stimulating hormone peptides inhibit TNF-alpha signaling in human dermal fibroblast cells.
        Peptides. 2006; 27: 421-430
        • Hiramoto K.
        • Kobayashi H.
        • Ishii M.
        • Sato E.
        • Inoue M.
        Increased alpha-melanocyte-stimulating hormone (alpha-MSH) levels and melanocortin receptors expression associated with pigmentation in an NC/Nga mouse model of atopic dermatitis.
        Exp Dermatol. 2010; 19: 132-136
        • Ichii-Jones F.
        • Lear J.T.
        • Heagerty A.H.
        • Smith A.G.
        • Hutchinson P.E.
        • Osborne J.
        • et al.
        Susceptibility to melanoma: influence of skin type and polymorphism in the melanocyte stimulating hormone receptor gene.
        J Invest Dermatol. 1998; 111: 218-221
        • Jackson E.
        • Heidl M.
        • Imfeld D.
        • Meeus L.
        • Schuetz R.
        • Campiche R.
        Discovery of a highly selective MC1R agonists pentapeptide to be used as a skin pigmentation enhancer and with potential anti-aging properties.
        Int J Mol Sci. 2019; 20: 6143
        • Jackson P.J.
        • Yu B.
        • Hunrichs B.
        • Thompson D.A.
        • Chai B.
        • Gantz I.
        • et al.
        Chimeras of the agouti-related protein: insights into agonist and antagonist selectivity of melanocortin receptors.
        Peptides. 2005; 26: 1978-1987
        • Jarrett S.G.
        • Wolf Horrell E.M.
        • Boulanger M.C.
        • D’Orazio J.A.
        Defining the contribution of MC1R physiological ligands to ATR phosphorylation at Ser435, a predictor of DNA repair in melanocytes.
        J Invest Dermatol. 2015; 135: 3086-3095
        • Jarrett S.G.
        • Wolf Horrell E.M.
        • Christian P.A.
        • Vanover J.C.
        • Boulanger M.C.
        • Zou Y.
        • et al.
        PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage.
        Mol Cell. 2014; 54: 999-1011
        • Johansson P.A.
        • Pritchard A.L.
        • Patch A.M.
        • Wilmott J.S.
        • Pearson J.V.
        • Waddell N.
        • et al.
        Mutation load in melanoma is affected by MC1R genotype.
        Pigment Cell Melanoma Res. 2017; 30: 255-258
        • Joshi A.D.
        • Li X.
        • Kraft P.
        • Han J.
        Hierarchical modeling of melanocortin 1 receptor variants with skin cancer risk.
        Genet Epidemiol. 2018; 42: 571-586
        • Kadekaro A.L.
        • Chen J.
        • Yang J.
        • Chen S.
        • Jameson J.
        • Swope V.B.
        • et al.
        Alpha-melanocyte-stimulating hormone suppresses oxidative stress through a p53-mediated signaling pathway in human melanocytes.
        Mol Cancer Res. 2012; 10: 778-786
        • Kadekaro A.L.
        • Leachman S.
        • Kavanagh R.J.
        • Swope V.
        • Cassidy P.
        • Supp D.
        • et al.
        Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation.
        FASEB J. 2010; 24: 3850-3860
        • Kennedy C.
        • ter Huurne J.
        • Berkhout M.
        • Gruis N.
        • Bastiaens M.
        • Bergman W.
        • et al.
        Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color.
        J Invest Dermatol. 2001; 117: 294-300
        • Khaled M.
        • Levy C.
        • Fisher D.E.
        Control of melanocyte differentiation by a MITF- PDE4D3 homeostatic circuit.
        Genes Dev. 2010; 24: 2276-2281
        • Kiss M.
        • Wlaschek M.
        • Brenneisen P.
        • Michel G.
        • Hommel C.
        • Lange T.S.
        • et al.
        Alpha-melanocyte stimulating hormone induces collagenase/matrix metalloproteinase-1 in human dermal fibroblasts.
        Biol Chem Hoppe Seyler. 1995; 376: 425-430
        • Kleiner S.
        • Braunstahl G.J.
        • Rüdrich U.
        • Gehring M.
        • Eiz-Vesper B.
        • Luger T.A.
        • et al.
        Regulation of melanocortin 1 receptor in allergic rhinitis in vitro and in vivo.
        Clin Exp Allergy. 2016; 46: 1066-1074
        • Koikov L.
        • Starner R.J.
        • Swope V.B.
        • Upadhyay P.
        • Hashimoto Y.
        • Freeman K.T.
        • et al.
        Development of hMC1R selective small agonists for sunless tanning and prevention of genotoxicity of UV in melanocytes.
        J Invest Dermatol. 2021; 141: 1819-1829
        • Langendonk J.G.
        • Balwani M.
        • Anderson K.E.
        • Bonkovsky H.L.
        • Anstey A.V.
        • Bissell D.M.
        • et al.
        Afamelanotide for erythropoietic protoporphyria.
        N Engl J Med. 2015; 373: 48-59
        • Levy C.
        • Khaled M.
        • Fisher D.E.
        MITF: master regulator of melanocyte development and melanoma oncogene.
        Trends Mol Med. 2006; 12: 406-414
        • Li X.
        • Mao W.
        • Chen J.
        • Goding C.R.
        • Cui R.
        • Xu Z.X.
        • et al.
        The protective role of MC1R in chromosome stability and centromeric integrity in melanocytes.
        Cell Death Discov. 2021; 7: 111
        • Loercher A.E.
        • Tank E.M.
        • Delston R.B.
        • Harbour J.W.
        MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A.
        J Cell Biol. 2005; 168: 35-40
        • Louphrasitthiphol P.
        • Ledaki I.
        • Chauhan J.
        • Falletta P.
        • Siddaway R.
        • Buffa F.M.
        • et al.
        MITF controls the TCA cycle to modulate the melanoma hypoxia response.
        Pigment Cell Melanoma Res. 2019; 32: 792-808
        • Louphrasitthiphol P.
        • Siddaway R.
        • Loffreda A.
        • Pogenberg V.
        • Friedrichsen H.
        • Schepsky A.
        • et al.
        Tuning transcription factor availability through acetylation-mediated genomic redistribution.
        Mol Cell. 2020; 79: 472-487.e10
        • Lowings P.
        • Yavuzer U.
        • Goding C.R.
        Positive and negative elements regulate a melanocyte-specific promoter.
        Mol Cell Biol. 1992; 12: 3653-3662
        • Luo L.F.
        • Shi Y.
        • Zhou Q.
        • Xu S.Z.
        • Lei T.C.
        Insufficient expression of the melanocortin-1 receptor by human dermal fibroblasts contributes to excess collagen synthesis in keloid scars.
        Exp Dermatol. 2013; 22: 764-766
        • Manganelli M.
        • Guida S.
        • Ferretta A.
        • Pellacani G.
        • Porcelli L.
        • Azzariti A.
        • et al.
        Behind the scene: exploiting MC1R in skin cancer risk and prevention.
        Genes. 2021; 12: 1093
        • Maresca V.
        • Flori E.
        • Picardo M.
        Skin phototype: a new perspective.
        Pigment Cell Melanoma Res. 2015; 28: 378-389
        • Miccadei S.
        • Pascucci B.
        • Picardo M.
        • Natali P.G.
        • Civitareale D.
        Identification of the minimal melanocyte-specific promoter in the melanocortin receptor 1 gene.
        J Exp Clin Cancer Res. 2008; 27: 71
        • Mitra D.
        • Luo X.
        • Morgan A.
        • Wang J.
        • Hoang M.P.
        • Lo J.
        • et al.
        An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background.
        Nature. 2012; 491: 449-453
        • Morgan M.D.
        • Pairo-Castineira E.
        • Rawlik K.
        • Canela-Xandri O.
        • Rees J.
        • Sims D.
        • et al.
        Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability.
        Nat Commun. 2018; 9: 5271
        • Moro O.
        • Ideta R.
        • Ifuku O.
        Characterization of the promoter region of the human melanocortin-1 receptor (MC1R) gene.
        Biochem Biophys Res Commun. 1999; 262: 452-460
        • Mountjoy K.G.
        • Robbins L.S.
        • Mortrud M.T.
        • Cone R.D.
        The cloning of a family of genes that encode the melanocortin receptors.
        Science. 1992; 257: 1248-1251
        • Mowlazadeh Haghighi S.
        • Zhou Y.
        • Dai J.
        • Sawyer J.R.
        • Hruby V.J.
        • Cai M.
        Replacement of Arg with Nle and modified D-Phe in the core sequence of MSHs, Ac-His-D-Phe-Arg-Trp-NH2, leads to hMC1R selectivity and pigmentation.
        Eur J Med Chem. 2018; 151: 815-823
        • Muffley L.A.
        • Zhu K.Q.
        • Engrav L.H.
        • Gibran N.S.
        • Hocking A.M.
        Spatial and temporal localization of the melanocortin 1 receptor and its ligand α-melanocyte-stimulating hormone during cutaneous wound repair.
        J Histochem Cytochem. 2011; 59: 278-288
        • Nasti T.H.
        • Timares L.
        MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer.
        Photochem Photobiol. 2015; 91: 188-200
        • Newton R.A.
        • Smit S.E.
        • Barnes C.C.
        • Pedley J.
        • Parsons P.G.
        • Sturm R.A.
        Activation of the cAMP pathway by variant human MC1R alleles expressed in HEK and in melanoma cells.
        Peptides. 2005; 26: 1818-1824
        • Palmer J.S.
        • Duffy D.L.
        • Box N.F.
        • Aitken J.F.
        • O'Gorman L.E.
        • Green A.C.
        • et al.
        Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?.
        Am J Hum Genet. 2000; 66: 176-186
        • Passeron T.
        • Bahadoran P.
        • Bertolotto C.
        • Chiaverini C.
        • Buscà R.
        • Valony G.
        • et al.
        Cyclic AMP promotes a peripheral distribution of melanosomes and stimulates melanophilin/Slac2-a and actin association.
        FASEB J. 2004; 18: 989-991
        • Patel M.P.
        • Cribb Fabersunne C.S.
        • Yang Y.K.
        • Kaelin C.B.
        • Barsh G.S.
        • Millhauser G.L.
        Loop-swapped chimeras of the agouti-related protein and the agouti signaling protein identify contacts required for melanocortin 1 receptor selectivity and antagonism.
        J Mol Biol. 2010; 404: 45-55
        • Pavan W.J.
        • Sturm R.A.
        The genetics of human skin and hair pigmentation.
        Annu Rev Genomics Hum Genet. 2019; 20: 41-72
        • Pellegrini C.
        • Botta F.
        • Massi D.
        • Martorelli C.
        • Facchetti F.
        • Gandini S.
        • et al.
        Mc1r variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.
        Lancet Child Adolesc Health. 2019; 3: 332-342
        • Price E.R.
        • Horstmann M.A.
        • Wells A.G.
        • Weilbaecher K.N.
        • Takemoto C.M.
        • Landis M.W.
        • et al.
        Alpha-melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg syndrome.
        J Biol Chem. 1998; 273: 33042-33047
        • Rees J.L.
        The melanocortin 1 receptor (MC1R): more than just red hair.
        Pigment Cell Res. 2000; 13: 135-140
        • Rees J.L.
        Genetics of hair and skin color.
        Annu Rev Genet. 2003; 37: 67-90
        • Rees J.L.
        The genetics of sun sensitivity in humans.
        Am J Hum Genet. 2004; 75: 739-751
        • Roberts D.W.
        • Newton R.A.
        • Beaumont K.A.
        • Helen Leonard J.
        • Sturm R.A.
        Quantitative analysis of MC1R gene expression in human skin cell cultures.
        Pigment Cell Res. 2006; 19: 76-89
        • Robinson S.
        • Dixon S.
        • August S.
        • Diffey B.
        • Wakamatsu K.
        • Ito S.
        • et al.
        Protection against UVR involves MC1R-mediated non-pigmentary and pigmentary mechanisms in vivo.
        J Invest Dermatol. 2010; 130: 1904-1913
        • Robles-Espinoza C.D.
        • Roberts N.D.
        • Chen S.
        • Leacy F.P.
        • Alexandrov L.B.
        • Pornputtapong N.
        • et al.
        Germline MC1R status influences somatic mutation burden in melanoma.
        Nat Commun. 2016; 7: 12064
        • Rodrigues A.R.
        • Almeida H.
        • Gouveia A.M.
        Intracellular signaling mechanisms of the melanocortin receptors: current state of the art.
        Cell Mol Life Sci. 2015; 72: 1331-1345
        • Roulin A.
        • Ducrest A.L.
        Association between melanism, physiology and behaviour: a role for the melanocortin system.
        Eur J Pharmacol. 2011; 660: 226-233
        • Sánchez-Laorden B.L.
        • Herraiz C.
        • Valencia J.C.
        • Hearing V.J.
        • Jiménez-Cervantes C.
        • García-Borrón J.C.
        Aberrant trafficking of human melanocortin 1 receptor variants associated with red hair and skin cancer: steady-state retention of mutant forms in the proximal Golgi.
        J Cell Physiol. 2009; 220: 640-654
        • Sánchez-Laorden B.L.
        • Jiménez-Cervantes C.
        • García-Borrón J.C.
        Regulation of human melanocortin 1 receptor signaling and trafficking by Thr-308 and Ser-316 and its alteration in variant alleles associated with red hair and skin cancer.
        J Biol Chem. 2007; 282: 3241-3251
        • Sánchez-Laorden B.L.
        • Sánchez-Más J.
        • Martínez-Alonso E.
        • Martínez-Menárguez J.A.
        • García-Borrón J.C.
        • Jiménez-Cervantes C.
        Dimerization of the human melanocortin 1 receptor: functional consequences and dominant-negative effects.
        J Invest Dermatol. 2006; 126: 172-181
        • Sánchez-Más J.
        • Hahmann C.
        • Gerritsen I.
        • García-Borrón J.C.
        • Jiménez-Cervantes C.
        Agonist-independent, high constitutive activity of the human melanocortin 1 receptor.
        Pigment Cell Res. 2004; 17: 386-395
        • Sánchez Más J.
        • Olivares Sánchez C.
        • Ghanem G.
        • Haycock J.
        • Lozano Teruel J.A.
        • García-Borrón J.C.
        • et al.
        Loss-of-function variants of the human melanocortin-1 receptor gene in melanoma cells define structural determinants of receptor function.
        Eur J Biochem. 2002; 269: 6133-6141
        • Scott M.C.
        • Wakamatsu K.
        • Ito S.
        • Kadekaro A.L.
        • Kobayashi N.
        • Groden J.
        • et al.
        Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation.
        J Cell Sci. 2002; 115: 2349-2355
        • Scott T.L.
        • Christian P.A.
        • Kesler M.V.
        • Donohue K.M.
        • Shelton B.
        • Wakamatsu K.
        • et al.
        Pigment-independent cAMP-mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation.
        Exp Dermatol. 2012; 21: 771-777
        • Seoane M.
        • Buhs S.
        • Iglesias P.
        • Strauss J.
        • Puller A.C.
        • Müller J.
        • et al.
        Lineage-specific control of TFIIH by MITF determines transcriptional homeostasis and DNA repair.
        Oncogene. 2019; 38: 3616-3635
        • Shaw G.
        • Morse S.
        • Ararat M.
        • Graham F.L.
        Preferential transformation of human neuronal cells by human adenoviruses and the origin of HEK 293 cells.
        FASEB J. 2002; 16: 869-871
        • Slominski A.
        • Tobin D.J.
        • Shibahara S.
        • Wortsman J.
        Melanin pigmentation in mammalian skin and its hormonal regulation.
        Physiol Rev. 2004; 84: 1155-1228
        • Smalley K.
        • Eisen T.
        The involvement of p38 mitogen-activated protein kinase in the alpha-melanocyte stimulating hormone (alpha-MSH)-induced melanogenic and anti-proliferative effects in B16 murine melanoma cells.
        FEBS Lett. 2000; 476: 198-202
        • Smith R.
        • Healy E.
        • Siddiqui S.
        • Flanagan N.
        • Steijlen P.M.
        • Rosdahl I.
        • et al.
        Melanocortin 1 receptor variants in an Irish population.
        J Invest Dermatol. 1998; 111: 119-122
        • Solé-Boldo L.
        • Raddatz G.
        • Schütz S.
        • Mallm J.P.
        • Rippe K.
        • Lonsdorf A.S.
        • et al.
        Single-cell transcriptomes of the human skin reveal age-related loss of fibroblast priming.
        Commun Biol. 2020; 3: 188
        • Strub T.
        • Giuliano S.
        • Ye T.
        • Bonet C.
        • Keime C.
        • Kobi D.
        • et al.
        Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma.
        Oncogene. 2011; 30: 2319-2332
        • Sturm R.A.
        • Duffy D.L.
        Human pigmentation genes under environmental selection.
        Genome Biol. 2012; 13: 248
        • Suzuki I.
        • Cone R.D.
        • Im S.
        • Nordlund J.
        • Abdel-Malek Z.A.
        Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis.
        Endocrinology. 1996; 137: 1627-1633
        • Suzuki I.
        • Tada A.
        • Ollmann M.M.
        • Barsh G.S.
        • Im S.
        • Lamoreux M.L.
        • et al.
        Agouti signaling protein inhibits melanogenesis and the response of human melanocytes to alpha-melanotropin.
        J Invest Dermatol. 1997; 108: 838-842
        • Swope V.
        • Alexander C.
        • Starner R.
        • Schwemberger S.
        • Babcock G.
        • Abdel-Malek Z.A.
        Significance of the melanocortin 1 receptor in the DNA damage response of human melanocytes to ultraviolet radiation.
        Pigment Cell Melanoma Res. 2014; 27: 601-610
        • Swope V.B.
        • Abdel-Malek Z.A.
        MC1R: front and center in the bright side of dark eumelanin and DNA repair.
        Int J Mol Sci. 2018; 19: 2667
        • Swope V.B.
        • Jameson J.A.
        • McFarland K.L.
        • Supp D.M.
        • Miller W.E.
        • McGraw D.W.
        • et al.
        Defining MC1R regulation in human melanocytes by its agonist α-melanocortin and antagonists agouti signaling protein and β-defensin 3.
        J Invest Dermatol. 2012; 132: 2255-2262
        • Swope V.B.
        • Starner R.J.
        • Rauck C.
        • Abdel-Malek Z.A.
        Endothelin-1 and α-melanocortin have redundant effects on global genome repair in UV-irradiated human melanocytes despite distinct signaling pathways.
        Pigment Cell Melanoma Res. 2020; 33: 293-304
        • Tagliabue E.
        • Fargnoli M.C.
        • Gandini S.
        • Maisonneuve P.
        • Liu F.
        • Kayser M.
        • et al.
        MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.
        Br J Cancer. 2015; 113: 354-363
        • Tagliabue E.
        • Gandini S.
        • Bellocco R.
        • Maisonneuve P.
        • Newton-Bishop J.
        • Polsky D.
        • et al.
        MC1R variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project.
        Cancer Manag Res. 2018; 10: 1143-1154
        • Tagliabue E.
        • Gandini S.
        • García-Borrón J.C.
        • Maisonneuve P.
        • Newton-Bishop J.
        • Polsky D.
        • et al.
        Association of melanocortin-1 receptor variants with pigmentary traits in humans: a pooled analysis from the M-skip project.
        J Invest Dermatol. 2016; 136: 1914-1917
        • Valverde P.
        • Healy E.
        • Jackson I.
        • Rees J.L.
        • Thody A.J.
        Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans.
        Nat Genet. 1995; 11: 328-330
        • Vazquez F.
        • Lim J.H.
        • Chim H.
        • Bhalla K.
        • Girnun G.
        • Pierce K.
        • et al.
        PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress.
        Cancer Cell. 2013; 23: 287-301
        • Villena J.A.
        New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond.
        FEBS Journal. 2015; 282: 647-672
        • Vivas-García Y.
        • Falletta P.
        • Liebing J.
        • Louphrasitthiphol P.
        • Feng Y.
        • Chauhan J.
        • et al.
        Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity.
        Mol Cell. 2020; 77: 120-137.e9
        • Walker W.P.
        • Gunn T.M.
        Shades of meaning: the pigment-type switching system as a tool for discovery.
        Pigment Cell Melanoma Res. 2010; 23: 485-495
        • Wang Y.
        • Lu H.
        • Fang C.
        • Xu J.
        Palmitoylation as a signal for delivery.
        Adv Exp Med Biol. 2020; 1248: 399-424
        • Williams P.F.
        • Olsen C.M.
        • Hayward N.K.
        • Whiteman D.C.
        Melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden.
        Int J Cancer. 2011; 129: 1730-1740
        • Wilson B.D.
        • Ollmann M.M.
        • Kang L.
        • Stoffel M.
        • Bell G.I.
        • Barsh G.S.
        Structure and function of ASP, the human homolog of the mouse agouti gene.
        Hum Mol Genet. 1995; 4: 223-230
        • Wolf Horrell E.M.
        • Boulanger M.C.
        • D’Orazio J.A.
        Melanocortin 1 receptor: structure, function, and regulation.
        Front Genet. 2016; 7: 95
        • Wolf Horrell E.M.
        • Jarrett S.G.
        • Carter K.M.
        • D’Orazio J.A.
        Divergence of cAMP signaling pathways mediating augmented nucleotide excision repair and pigment induction in melanocytes.
        Exp Dermatol. 2017; 26: 577-584
        • Yang Y.
        • Harmon C.M.
        Molecular signatures of human melanocortin receptors for ligand binding and signaling.
        Biochim Biophys Acta Mol Basis Dis. 2017; 1863: 2436-2447
        • Yin K.
        • Sturm R.A.
        • Smith A.G.
        MC1R and NR4A receptors in cellular stress and DNA repair: implications for UVR protection.
        Exp Dermatol. 2014; 23: 449-452
        • Zanna P.
        • Maida I.
        • Grieco C.
        • Guida S.
        • Turpin Sevilla M.C.
        • De Summa S.
        • et al.
        Three novel human sporadic melanoma cell lines: signaling pathways controlled by MC1R, BRAF and β-catenins.
        J Biol Regul Homeost Agents. 2013; 27: 131-141