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Melanocortin 1 Receptor (MC1R) as a Global Regulator of Cutaneous UV Responses: Molecular Interactions and Opportunities for Melanoma Prevention

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Skin Stress Response Pathways

Abstract

UV radiation is a pervasive environmental agent that affects the skin in complex ways . It benefits human health by its contribution to the biosynthesis of vitamin D in the skin, however it also is a major carcinogen responsible for millions of skin cancers diagnosed each year. One of the most important physiologic responses recruited with UV exposure is the melanocortin signaling axis. This pathway, initiated by melanocortins such as melanocyte stimulating hormone (α-MSH) or adrenocorticotropic hormone (ACTH), is dependent on the signaling function of the melanocortin 1 receptor (MC1R), a Gs protein-coupled cell surface receptor found on melanocytes in the skin. MC1R mediates its downstream UV-protective responses through activation of adenylyl cyclase and production of the second messenger cAMP. In melanocytes, cAMP stimulation leads to improved survival and UV-defensive sequelae. Here, we review how MC1R signaling protects melanocytes from UV-induced malignant degeneration, focusing on recent insights into molecular links between MC1R signaling and the nucleotide excision repair (NER) genome maintenance pathway. Finally, we highlight how insights into the MC1R UV protective response may facilitate the development of rational melanoma -protective strategies.

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References

  • Abdel-Malek ZA, Kadekaro AL, Kavanagh RJ, Todorovic A, Koikov LN, McNulty JC, Jackson PJ, Millhauser GL, Schwemberger S, Babcock G, Haskell-Luevano C, Knittel JJ (2006) Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. Faseb J 20(9):1561–1563

    Article  CAS  PubMed  Google Scholar 

  • Abdel-Malek ZA, Ruwe A, Kavanagh-Starner R, Kadekaro AL, Swope V, Haskell-Luevano C, Koikov L, Knittel JJ (2009) alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes. Pigm Cell Melanoma Res 22(5):635–644

    Article  CAS  Google Scholar 

  • Arnett E, Seveau S (2011) The multifaceted activities of mammalian defensins. Curr Pharm Des 17(38):4254–4269

    Article  CAS  PubMed  Google Scholar 

  • Beaumont KA, Newton RA, Smit DJ, Leonard JH, Stow JL, Sturm RA (2005) Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. Hum Mol Genet 14(15):2145–2154

    Article  CAS  PubMed  Google Scholar 

  • Beaumont KA, Smit DJ, Liu YY, Chai E, Patel MP, Millhauser GL, Smith JJ, Alewood PF, Sturm RA (2012) Melanocortin-1 receptor-mediated signalling pathways activated by NDP-MSH and HBD3 ligands. Pigm Cell Melanoma Res 25(3):370–374

    Article  CAS  Google Scholar 

  • Bohm M, Wolff I, Scholzen TE, Robinson SJ, Healy E, Luger TA, Schwarz T, Schwarz A (2005) alpha-Melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage. J Biol Chem 280(7):5795–5802

    Article  PubMed  Google Scholar 

  • Box NF, Wyeth JR, O’Gorman LE, Martin NG, Sturm RA (1997) Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum Mol Genet 6(11):1891–1897

    Article  CAS  PubMed  Google Scholar 

  • Brash DE (2015) UV signature mutations. Photochem Photobiol 91(1):15–26

    Article  CAS  PubMed  Google Scholar 

  • Candille SI, Kaelin CB, Cattanach BM, Yu B, Thompson DA, Nix MA, Kerns JA, Schmutz SM, Millhauser GL, Barsh GS (2007) A -defensin mutation causes black coat color in domestic dogs. Science 318(5855):1418–1423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi K, Lazovich D, Southwell B, Forster J, Rolnick SJ, Jackson J (2010) Prevalence and characteristics of indoor tanning use among men and women in the United States. Arch Dermatol 146(12):1356–1361

    Article  PubMed  Google Scholar 

  • Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D’Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE (2007) Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 128(5):853–864

    Article  CAS  PubMed  Google Scholar 

  • D’Orazio JA, Nobuhisa T, Cui R, Arya M, Spry M, Wakamatsu K, Igras V, Kunisada T, Granter SR, Nishimura EK, Ito S, Fisher DE (2006) Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature 443(7109):340–344

    Article  PubMed  Google Scholar 

  • DiGiovanna JJ, Kraemer KH (2012) Shining a light on xeroderma pigmentosum. J Invest Dermatol 132(3 Pt 2):785–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duffy DL, Box NF, Chen W, Palmer JS, Montgomery GW, James MR, Hayward NK, Martin NG, Sturm RA (2004) Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. Hum Mol Genet 13(4):447–461

    Article  CAS  PubMed  Google Scholar 

  • Fisher DE, James WD (2010) Indoor tanning–science, behavior, and policy. N Engl J Med 363(10):901–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Borron JC, Sanchez-Laorden BL, Jimenez-Cervantes C (2005) Melanocortin-1 receptor structure and functional regulation. Pigm Cell Res 18(6):393–410

    CAS  Google Scholar 

  • Glaser R, Navid F, Schuller W, Jantschitsch C, Harder J, Schroder JM, Schwarz A, Schwarz T (2009) UV-B radiation induces the expression of antimicrobial peptides in human keratinocytes in vitro and in vivo. J Allergy Clin Immunol 123(5):1117–1123

    Article  PubMed  Google Scholar 

  • Grichnik JM, Burch JA, Burchette J, Shea CR (1998) The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol 111(2):233–238

    Article  CAS  PubMed  Google Scholar 

  • Hauser JE, Kadekaro AL, Kavanagh RJ, Wakamatsu K, Terzieva S, Schwemberger S, Babcock G, Rao MB, Ito S, Abdel-Malek ZA (2006) Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes. Pigm Cell Res 19(4):303–314

    Article  CAS  Google Scholar 

  • Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361(15):1475–1485

    Article  CAS  PubMed  Google Scholar 

  • Holick MF (2008) Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol 624:1–15

    Article  CAS  PubMed  Google Scholar 

  • Hou L, Pavan WJ, Shin MK, Arnheiter H (2004) Cell-autonomous and cell non-autonomous signaling through endothelin receptor B during melanocyte development. Development 131(14):3239–3247

    Article  CAS  PubMed  Google Scholar 

  • Jagirdar K, Yin K, Harrison M, Lim W, Muscat GE, Sturm RA, Smith AG (2013) The NR4A2 nuclear receptor is recruited to novel nuclear foci in response to UV irradiation and participates in nucleotide excision repair. PLoS ONE 8(11):e78075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jarrett SG, Wolf Horrell EM, Christian PA, Vanover JC, Boulanger MC, Zou Y, D’Orazio JA (2014) PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage. Mol Cell 54(6):999–1011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jarrett SG, Wolf Horrell EM, Boulanger MC, D’Orazio JA (2015) Defining the contribution of MC1R physiological ligands to ATR phosphorylation at Ser435, a predictor of DNA repair in melanocytes. J Invest Dermatol

    Google Scholar 

  • Jordan SA, Jackson IJ (1998) Melanocortin receptors and antagonists regulate pigmentation and body weight. BioEssays 20(8):603–606

    Article  CAS  PubMed  Google Scholar 

  • Kadekaro AL, Chen J, Yang J, Chen S, Jameson J, Swope VB, Cheng T, Kadakia M, Abdel-Malek Z (2012) Alpha-melanocyte-stimulating hormone suppresses oxidative stress through a p53-mediated signaling pathway in human melanocytes. Mol Cancer Res 10(6):778–786

    Article  CAS  PubMed  Google Scholar 

  • Kaiser V, Diamond G (2000) Expression of mammalian defensin genes. J Leukoc Biol 68(6):779–784

    CAS  Google Scholar 

  • Kennedy C, ter Huurne J, Berkhout M, Gruis N, Bastiaens M, Bergman W, Willemze R, Bavinck JN (2001) 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 117(2):294–300

    Article  CAS  PubMed  Google Scholar 

  • Khaled M, Levy C, Fisher DE (2010) Control of melanocyte differentiation by a MITF-PDE4D3 homeostatic circuit. Genes Dev 24(20):2276–2281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krutmann J, Morita A, Chung JH (2012) Sun exposure: what molecular photodermatology tells us about its good and bad sides. J Invest Dermatol 132(3 Pt 2):976–984

    Article  CAS  PubMed  Google Scholar 

  • Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Lee RS, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CW, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499(7457):214–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Yin M, Wang LE, Amos CI, Zhu D, Lee JE, Gershenwald JE, Grimm EA, Wei Q (2013) Polymorphisms of nucleotide excision repair genes predict melanoma survival. J Invest Dermatol 133(7):1813–1821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linos E, Swetter SM, Cockburn MG, Colditz GA, Clarke CA (2009) Increasing burden of melanoma in the United States. J Invest Dermatol 129(7):1666–1674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lippens S, Hoste E, Vandenabeele P, Agostinis P, Declercq W (2009) Cell death in the skin. Apoptosis 14:549–569

    Google Scholar 

  • Miyamura Y, Coelho SG, Wolber R, Miller SA, Wakamatsu K, Zmudzka BZ, Ito S, Smuda C, Passeron T, Choi W, Batzer J, Yamaguchi Y, Beer JZ, Hearing VJ (2007) Regulation of human skin pigmentation and responses to ultraviolet radiation. Pigm Cell Res 20(1):2–13

    Article  CAS  Google Scholar 

  • Narayanan DL, Saladi RN, Fox JL (2010) Ultraviolet radiation and skin cancer. Int J Dermatol 49(9):978–986

    Article  PubMed  Google Scholar 

  • Nasti TH, Timares L (2015) MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer. Photochem Photobiol 91(1):188–200

    Article  CAS  PubMed  Google Scholar 

  • Nilsen LT, Aalerud TN, Hannevik M, Veierod MB (2011) UVB and UVA irradiances from indoor tanning devices. Photochem Photobiol Sci 10:1129–1136

    Google Scholar 

  • Nordlund JJ (2007) The melanocyte and the epidermal melanin unit: an expanded concept. Dermatol Clin 25(3):271–281, vii

    Google Scholar 

  • Nouspikel T (2009) DNA repair in mammalian cells: nucleotide excision repair: variations on versatility. Cell Mol Life Sci 66(6):994–1009

    Article  CAS  PubMed  Google Scholar 

  • Ollmann MM, Lamoreux ML, Wilson BD, Barsh GS (1998) Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo. Genes Dev 12(3):316–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordonez GR, Bignell GR, Ye K, Alipaz J, Bauer MJ, Beare D, Butler A, Carter RJ, Chen L, Cox AJ, Edkins S, Kokko-Gonzales PI, Gormley NA, Grocock RJ, Haudenschild CD, Hims MM, James T, Jia M, Kingsbury Z, Leroy C, Marshall J, Menzies A, Mudie LJ, Ning Z, Royce T, Schulz-Trieglaff OB, Spiridou A, Stebbings LA, Szajkowski L, Teague J, Williamson D, Chin L, Ross MT, Campbell PJ, Bentley DR, Futreal PA, Stratton MR (2010) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463(7278):191–196

    Article  CAS  PubMed  Google Scholar 

  • Premi S, Wallisch S, Mano CM, Weiner AB, Bacchiocchi A, Wakamatsu K, Bechara EJ, Halaban R, Douki T, Brash DE (2015) Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. Science 347(6224):842–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scharer OD (2013) Nucleotide excision repair in eukaryotes. Cold Spring Harb Perspect Biol 5(10):a012609

    Article  PubMed  PubMed Central  Google Scholar 

  • Scherer D, Kumar R (2010) Genetics of pigmentation in skin cancer–a review. Mutat Res 705(2):141–153

    Article  CAS  PubMed  Google Scholar 

  • Scott TL, Christian PA, Kesler MV, Donohue KM, Shelton B, Wakamatsu K, Ito S, D’Orazio J (2012) Pigment-independent cAMP-mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation. Exp Dermatol 21(10):771–777

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, Dummer R, North J, Pincus L, Ruben B, Rickaby W, D’Arrigo C, Robson A, Bastian BC (2015) The genetic evolution of melanoma from precursor lesions. N Engl J Med 373(20):1926–1936

    Article  PubMed  Google Scholar 

  • Simard EP, Ward EM, Siegel R, Jemal A (2012) Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin 62:118–128

    Google Scholar 

  • Slominski A, Tobin DJ, Shibahara S, Wortsman J (2004) Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84(4):1155–1228

    Article  CAS  PubMed  Google Scholar 

  • Sommer L (2011) Generation of melanocytes from neural crest cells. Pigm Cell Melanoma Res 24(3):411–421

    Article  CAS  Google Scholar 

  • Song X, Mosby N, Yang J, Xu A, Abdel-Malek Z, Kadekaro AL (2009) Alpha-MSH activates immediate defense responses to UV-induced oxidative stress in human melanocytes. Pigm Cell Melanoma Res 22(6):809–818

    Article  CAS  Google Scholar 

  • Suzuki I, Tada A, Ollmann MM, Barsh GS, Im S, Lamoreux ML, Hearing VJ, Nordlund JJ, Abdel-Malek ZA (1997) Agouti signaling protein inhibits melanogenesis and the response of human melanocytes to alpha-melanotropin. J Invest Dermatol 108(6):838–842

    Article  CAS  PubMed  Google Scholar 

  • Sviderskaya EV, Hill SP, Balachandar D, Barsh GS, Bennett DC (2001) Agouti signaling protein and other factors modulating differentiation and proliferation of immortal melanoblasts. Dev Dyn 221(4):373–379

    Article  CAS  PubMed  Google Scholar 

  • Swope VB, Jameson JA, McFarland KL, Supp DM, Miller WE, McGraw DW, Patel MA, Nix MA, Millhauser GL, Babcock GF, Abdel-Malek ZA (2012) Defining MC1R regulation in human melanocytes by its agonist alpha-melanocortin and antagonists agouti signaling protein and beta-defensin 3. J Invest Dermatol 132(9):2255–2262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swope V, Alexander C, Starner R, Schwemberger S, Babcock G, Abdel-Malek ZA (2014) Significance of the melanocortin 1 receptor in the DNA damage response of human melanocytes to ultraviolet radiation. Pigm Cell Melanoma Res 27(4):601–610

    Article  CAS  Google Scholar 

  • Tomita Y, Suzuki T (2004) Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet 131C(1):75–81

    Article  PubMed  Google Scholar 

  • Ullrich SE, Byrne SN (2012) The immunologic revolution: photoimmunology. J Invest Dermatol 132(3 Pt 2):896–905

    Article  CAS  PubMed  Google Scholar 

  • Widlund HR, Fisher DE (2003) Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival. Oncogene 22(20):3035–3041

    Article  CAS  PubMed  Google Scholar 

  • Wolf Horrell E, D’Orazio J (2014) UV-independent induction of beta defensin 3 in neonatal human skin explants. F1000Res 3:288

    Google Scholar 

  • Yamaguchi Y, Hearing VJ (2009) Physiological factors that regulate skin pigmentation. BioFactors 35(2):193–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We acknowledge Dr. Stuart Jarrett for insights and key experimental discoveries seminal to our understanding of the molecular links between the melanocortin signaling axis and melanocyte UV resistance and DNA repair. We are grateful for support from the National Cancer Institute (R01 CA131075), the Melanoma Research Alliance (MRA) and the Regina Drury Endowment for Pediatric Research as well as T32CA165990 which supported E.W.H.

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Authors and Affiliations

  1. Department of Physiology, University of Kentucky College of Medicine, Lexington, USA

    Erin M. Wolf Horrell

  2. Departments of Pediatrics, Toxicology and Cancer Biology, Physiology, and Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Markey Cancer Center, 800 Rose Street, Combs 204, Lexington, KY, 40536-0096, USA

    John A. D’Orazio

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Correspondence to John A. D’Orazio .

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  1. Department of Pharmacology and Toxicology, College of Pharmacy & The University of Arizona Cancer Center, Department of Pharmacology and Toxicology, TUCSON, Arizona, USA

    Georg T. Wondrak

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Wolf Horrell, E.M., D’Orazio, J.A. (2016). Melanocortin 1 Receptor (MC1R) as a Global Regulator of Cutaneous UV Responses: Molecular Interactions and Opportunities for Melanoma Prevention. In: Wondrak, G. (eds) Skin Stress Response Pathways. Springer, Cham. https://doi.org/10.1007/978-3-319-43157-4_7

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