Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix

Oncogene volume 21, pages 8037–8046 (2002)Cite this article

Abstract

Pigmentation is a significant determinant of individual susceptibility to cutaneous melanoma, with fair skinned subjects at highest risk of developing this neoplasm. Melanocortin 1 receptor (MC1R) gene variants alter pigment synthesis in vivo, and are causally associated with red hair and fair skin in humans. MC1R variants are more frequent in subjects with melanoma, and increase the risk of developing this tumour in sporadic and familial cases. MC1R variants may predispose to melanoma as a result of alterations in skin pigmentation (which affords less protection against incident ultraviolet radiation). However, melanoma cells synthesize and release alpha-melanocyte stimulating hormone (αMSH, the ligand for MC1R), therefore MC1R variants could alter the autocrine effects of αMSH on melanoma cell behaviour, thereby affecting early melanoma development and progression via non-pigmentary mechanisms. B16G4F melanoma cells, which are functionally null at Mc1r, were stably transfected with wild type and variant (Arg151Cys, Arg160Trp, and Asp294His) human MC1R. At similar MC1 receptor numbers per cell, αMSH increased intracellular cAMP in wild type MC1R transfected melanoma cells, but the cAMP response was compromised in the variant MC1R transfected clones. In growth inhibition experiments, αMSH significantly reduced growth of wild type MC1R transfected cells, but had no effect on cells transfected with variant MC1R. In addition, binding to fibronectin was significantly reduced by αMSH in the wild type transfectants whereas this was not observed in the variant transfected clones; binding to laminin was not affected by αMSH in this cell line. These results provide evidence for differences in melanoma cell behaviour secondary to MC1R variants, and suggest an alternative non-pigmentary mechanism whereby MC1R variants could modify melanoma susceptibility or progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Abdel-Malek ZA . 2001 Cell. Mol. Life Sci. 58: 434–441

  • Bastiaens MT, ter Huurne JA, Kielich C, Gruis NA, Westendorp RG, Vermeer BJ, Bavinck JN . 2001 Am. J. Hum. Genet. 68: 884–894

  • Box NF, Duffy DL, Chen W, Stark M, Martin NG, Sturm RA, Hayward NK . 2001b Am. J. Hum. Genet. 69: 765–773

  • Box NF, Duffy DL, Irving RE, Russell A, Chen W, Griffyths LR, Parsons PG, Green AC, Sturm RA . 2001a J. Invest. Dermatol. 116: 224–229

  • Box NF, Wyeth JR, O'Gorman LE, Martin NG, Sturm RA . 1997 Hum. Mol. Genet. 6: 1891–1897

  • Chluba-de Tapia J, Bagutti C, Wikberg JS, Chhajlani V, Eberle AN . 1995 J. Recept. Signal Transduct. Res. 15: 43–53

  • Chluba-de Tapia J, Bagutti C, Cotti R, Eberle AN . 1996 J. Cell Sci. 109: 2023–2030

  • Clark EA, Golub TR, Lander ES, Hynes RO . 2000 Nature 406: 532–535

  • Corbin JD, Francis SH . 1999 J. Biol. Chem. 274: 13729–13732

  • Crombie IK . 1979 Br. J. Cancer 40: 185–193

  • Flanagan N, Healy E, Ray A, Philips S, Todd C, Jackson IJ, Birch-Machin MA, Rees JL . 2000 Hum. Mol. Genet. 9: 2531–2537

  • Ghanem G, Verstegen J, Libert A, Arnould R, Lejeune F . 1989 Pigment Cell Res. 2: 519–523

  • Haake A, Holbrooke K . 1999 Fitzpatrick's Dermatology in General Medicine 5th edn Freedberg IM et al., (eds) New York: McGraw-Hill pp. 70–113

    Google Scholar 

  • Harding RM, Healy E, Ray AJ, Ellis NS, Flanagan N, Todd C, Dixon C, Sajantila A, Jackson IJ, Birch-Machin MA, Rees JL . 2000 Am. J. Hum. Genet. 66: 1351–1361

  • Haycock JW, Wagner M, Morandini R, Ghanem G, Rennie IG, MacNeil S . 1999 J. Invest. Dermatol. 113: 560–566

  • Healy E, Flannagan N, Ray A, Todd C, Jackson IJ, Matthews JN, Birch-Machin MA, Rees JL . 2000 Lancet 355: 1072–1073

  • Healy E, Jordan SA, Budd PS, Suffolk R, Rees JL, Jackson IJ . 2001 Hum. Mol. Genet. 10: 2397–2402

  • Hedley SJ, Gawkrodger DJ, Weetman AP, Morandini R, Boeynaems JM, Ghanem G, MacNeil S . 1998 Br. J. Dermatol. 138: 536–543

  • Humphries MJ, Olden K, Yamada KM . 1986 Science 233: 467–470

  • Iwamoto Y, Robey FA, Graf J, Sasaki M, Kleinman HK, Yamada Y, Martin GR . 1987 Science 238: 1132–1134

  • Jiang J, Sharma SD, Nakamura S, Lai JY, Fink JL, Hruby VJ, Hadley ME . 1995 Pigment Cell Res. 8: 314–323

  • Jiminez-Cervantes C, Olivares C, González P, Morandini R, Ghanem G, García-Borrón JC . 2001 J. Invest. Dermatol. 117: 156–158

  • Kaidbey KH, Agin PP, Sayre RM, Kligman AM . 1979 J. Am. Acad. Dermatol. 1: 249–260

  • Karjalainen JM, Eskelinen MJ, Nordling S, Lipponen PK, Alhava EM, Kosma VM . 1998 Br. J. Cancer 77: 1917–1925

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

  • Kijas JM, Moller M, Plastow G, Andersson L . 2001 Genetics 158: 779–785

  • Klungland H, Vage DI, Gomez-Raya L, Adalsteinsson S, Lien S . 1995 Mamm. Genome. 6: 636–639

  • Legros F, Coel J, Doyen A, Hanson P, Van Tieghem N, Vercammen-Grandjean A, Fruhling J, Lejeune FJ . 1981 Cancer Res. 41: 1539–1544

  • Loir B, Sales F, Deraemaecker R, Morandini R, Garcia-Borron JC, Ghanem G . 1998 Eur. J. Cancer 34: 424–426

  • Luger TA, Brzoska T, Scholzen TE, Kalden D, Sunderkotter C, Armstrong C, Ansel J . 2000 Ann. N.Y. Acad. Sci. 917: 232–238

  • Lunec J, Pieron C, Sherbet GV, Thody AJ . 1990 Pathobiology 58: 193–197

  • Marklund L, Moller MJ, Sandberg K, Andersson L . 1996 Mamm. Genome. 7: 895–899

  • Morandini R, Boeynaems JM, Hedley SJ, MacNeil S, Ghanem G . 1998 J. Cell Physiol. 175: 276–282

  • Moretti S, Massobrio R, Brogelli L, Novelli M, Giannotti B, Bernengo MG . 1990 J. Invest. Dermatol. 95: 320–324

  • Mountjoy KG, Robbins LS, Mortrud MT, Cone RD . 1992 Science 257: 1248–1251

  • Murata J, Ayukawa K, Ogasawara M, Fujii H, Saiki I . 1997 Invasion Metastasis 17: 82–93

  • Nesbit M, Herlyn M . 1994 Invasion Metastasis 14: 131–146

  • Neumann AG, Nagaeva O, Mandrika I, Petrovska R, Muceniece R, Mincheva-Nilsson L, Wikberg JE . 2001 Clin. Exp. Immunol. 126: 441–446

  • Newton JM, Wilkie AL, He L, Jordan SA, Metallinos DL, Holmes NG, Jackson IJ, Barsh GS . 2000 Mamm. Genome. 11: 24–30

  • Palmer JS, Duffy DL, Box NF, Aitken JF, O'Gorman LE, Green AC, Hayward NK, Martin NG, Sturm RA . 2000 Am. J. Hum. Genet. 66: 176–186

  • Rampen FH, Fleuren BA, de Boo TM, Lemmens WA . 1988 Arch. Dermatol. 124: 885–888

  • Ramsay JA, From L, Iscoe NA, Kahn HJ . 1995 J. Invest. Dermatol. 105: 22–26

  • Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, Mountjoy KG, Cone RD . 1993 Cell 72: 827–834

  • Romero-Graillet C, Aberdam E, Biagoli N, Massabni W, Ortonne JP, Ballotti R . 1996 J. Biol. Chem. 271: 28052–28056

  • Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, Hadley ME . 1980 Proc. Natl. Acad. Sci. USA 77: 5754–5758

  • Schioth HB, Phillips SR, Rudzish R, Birch-Machin MA, Wikberg JE, Rees JL . 1999 Biochem. Biophys. Res. Commun. 260: 488–491

  • Smalley K, Eisen T . 2000 FEBS Lett. 476: 198–202

  • Smith R, Healy E, Siddiqui S, Flanagan N, Steijlen PM, Rosdahl I, Jacques JP, Rogers S, Turner R, Jackson IJ, Birch-Machin MA, Rees JL . 1998 J. Invest. Dermatol. 111: 119–122

  • Solca FF, Chluba-de Tapia J, Iwata K, Eberle AN . 1993 FEBS Lett. 322: 177–180

  • Takeuchi S, Suzuki H, Yabuuchi M, Takahashi S . 1996 Biochim. Biophys. Acta 1308: 164–168

  • Terranova VP, Williams JE, Liotta LA, Martin GR . 1984 Science 226: 982–985

  • Thody AJ, Hunt G, Donatien PD, Todd C . 1993 Ann. N.Y. Acad. Sci. 680: 381–390

  • Vage DI, Klungland H, Lu D, Cone RD . 1999 Mamm. Genome. 10: 39–43

  • Vage DI, Lu D, Klungland H, Lien S, Adalsteinsson S, Cone RD . 1997 Nat. Genet. 15: 311–315

  • Valverde P, Healy E, Jackson I, Rees JL, Thody AJ . 1995 Nat. Genet. 11: 328–330

  • Valverde P, Healy E, Sikkink S, Haldane F, Thody AJ, Carothers A, Jackson IJ, Rees JL . 1996 Hum. Mol. Genet. 5: 1663–1666

  • van der Velden PA, Sandkuijl LA, Bergman W, Pavel S, van Mourik L, Frants RR, Gruis NA . 2001 Am. J. Hum. Genet. 69: 774–779

  • Weinstock MA, Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE . 1991 Am. J. Epidemiol. 133: 240–245

Download references

Acknowledgements

We are grateful to A Eberle for providing the B16G4F cell line, to S Phillips and JL Rees for providing the original pCR3.1 plasmids with wild type and variant MC1R, and to P Friedmann and LM Holden-Dye for helpful advice. The work was supported by grants from the Medical Research Council, the Wessex Medical Trust (HOPE), and the British Medical Association. E Healy is a Medical Research Council Senior Clinical Fellow.

Author information

Authors and Affiliations

  1. Dermatopharmacology, University of Southampton, Southampton General Hospital, UK

    Samantha J Robinson & Eugene Healy

Authors
  1. Samantha J Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eugene Healy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eugene Healy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robinson, S., Healy, E. Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix. Oncogene 21, 8037–8046 (2002). https://doi.org/10.1038/sj.onc.1205913

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205913

Keywords

This article is cited by

Search

Advanced search

Quick links