Letter | Published:

Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning


Ultraviolet-light (UV)-induced tanning is defective in numerous ‘fair-skinned’ individuals, many of whom contain functional disruption of the melanocortin 1 receptor (MC1R)1,2,3. Although this suggested a critical role for the MC1R ligand melanocyte stimulating hormone (MSH) in this response, a genetically controlled system has been lacking in which to determine the precise role of MSH–MC1R. Here we show that ultraviolet light potently induces expression of MSH in keratinocytes, but fails to stimulate pigmentation in the absence of functional MC1R in red/blonde-haired Mc1re/e mice. However, pigmentation could be rescued by topical application of the cyclic AMP agonist forskolin, without the need for ultraviolet light, demonstrating that the pigmentation machinery is available despite the absence of functional MC1R. This chemically induced pigmentation was protective against ultraviolet-light-induced cutaneous DNA damage and tumorigenesis when tested in the cancer-prone, xeroderma-pigmentosum-complementation-group-C-deficient genetic background. These data emphasize the essential role of intercellular MSH signalling in the tanning response, and suggest a clinical strategy for topical small-molecule manipulation of pigmentation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    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 257, 1248–1251 (1992)

  2. 2

    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. Nature Genet. 11, 328–330 (1995)

  3. 3

    Rouzaud, F., Kadekaro, A. L., Abdel-Malek, Z. A. & Hearing, V. J. MC1R and the response of melanocytes to ultraviolet radiation. Mutat. Res. 571, 133–152 (2005)

  4. 4

    Sturm, R. A. et al. Genetic association and cellular function of MC1R variant alleles in human pigmentation. Ann. NY Acad. Sci. 994, 348–358 (2003)

  5. 5

    Van Raamsdonk, C. D., Fitch, K. R., Fuchs, H., de Angelis, M. H. & Barsh, G. S. Effects of G-protein mutations on skin color. Nature Genet. 36, 961–968 (2004)

  6. 6

    Lamason, R. L. et al. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 310, 1782–1786 (2005)

  7. 7

    Naysmith, L. et al. Quantitative measures of the effect of the melanocortin 1 receptor on human pigmentary status. J. Invest. Dermatol. 122, 423–428 (2004)

  8. 8

    Rees, J. L. The genetics of sun sensitivity in humans. Am. J. Hum. Genet. 75, 739–751 (2004)

  9. 9

    Eller, M. S., Yaar, M. & Gilchrest, B. A. DNA damage and melanogenesis. Nature 372, 413–414 (1994)

  10. 10

    Eller, M. S., Ostrom, K. & Gilchrest, B. A. DNA damage enhances melanogenesis. Proc. Natl Acad. Sci. USA 93, 1087–1092 (1996)

  11. 11

    Price, E. R. et al. α-melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg syndrome. J. Biol. Chem. 273, 33042–33047 (1998)

  12. 12

    Wintzen, M., Yaar, M., Burbach, J. P. & Gilchrest, B. A. Proopiomelanocortin gene product regulation in keratinocytes. J. Invest. Dermatol. 106, 673–678 (1996)

  13. 13

    Corre, S. et al. UV-induced expression of key component of the tanning process, the POMC and MC1R genes, is dependent on the p-38-activated upstream stimulating factor-1 (USF-1). J. Biol. Chem. 279, 51226–51233 (2004)

  14. 14

    Chakraborty, A. K. et al. Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B. Biochim. Biophys. Acta 1313, 130–138 (1996)

  15. 15

    Kunisada, T. et al. Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor. J. Exp. Med. 187, 1565–1573 (1998)

  16. 16

    Seamon, K. B. & Daly, J. W. Forskolin: a unique diterpene activator of cyclic AMP-generating systems. J. Cyclic Nucleotide Res. 7, 201–224 (1981)

  17. 17

    Wakamatsu, K. & Ito, S. Advanced chemical methods in melanin determination. Pigment Cell Res. 15, 174–183 (2002)

  18. 18

    Lin, C. B. et al. Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation. J. Invest. Dermatol. 119, 1330–1340 (2002)

  19. 19

    Kobayashi, N. et al. Supranuclear melanin caps reduce ultraviolet induced DNA photoproducts in human epidermis. J. Invest. Dermatol. 110, 806–810 (1998)

  20. 20

    Bayerl, C., Taake, S., Moll, I. & Jung, E. G. Characterization of sunburn cells after exposure to ultraviolet light. Photodermatol. Photoimmunol. Photomed. 11, 149–154 (1995)

  21. 21

    Sands, A. T., Abuin, A., Sanchez, A., Conti, C. J. & Bradley, A. High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC. Nature 377, 162–165 (1995)

  22. 22

    Sakai, C. et al. Modulation of murine melanocyte function in vitro by agouti signal protein. EMBO J. 16, 3544–3552 (1997)

  23. 23

    Hirobe, T. Basic fibroblast growth factor stimulates the sustained proliferation of mouse epidermal melanoblasts in a serum-free medium in the presence of dibutyryl cyclic AMP and keratinocytes. Development 114, 435–445 (1992)

  24. 24

    Cook, A. L. et al. Human melanoblasts in culture: expression of BRN2 and synergistic regulation by fibroblast growth factor-2, stem cell factor, and endothelin-3. J. Invest. Dermatol. 121, 1150–1159 (2003)

  25. 25

    Lassalle, M. W. et al. Effects of melanogenesis-inducing nitric oxide and histamine on the production of eumelanin and pheomelanin in cultured human melanocytes. Pigment Cell Res. 16, 81–84 (2003)

  26. 26

    Grichnik, J. M., Burch, J. A., Burchette, J. & Shea, C. R. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J. Invest. Dermatol. 111, 233–238 (1998)

  27. 27

    Kadekaro, A. L. et al. α-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. Cancer Res. 65, 4292–4299 (2005)

  28. 28

    Galibert, M. D., Carreira, S. & Goding, C. R. The Usf-1 transcription factor is a novel target for the stress-responsive p38 kinase and mediates UV-induced Tyrosinase expression. EMBO J. 20, 5022–5031 (2001)

  29. 29

    Park, S. B., Suh, D. H. & Youn, J. I. A long-term time course of colorimetric evaluation of ultraviolet light-induced skin reactions. Clin. Exp. Dermatol. 24, 315–320 (1999)

  30. 30

    Nishimura, E. K., Granter, S. R. & Fisher, D. E. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307, 720–724 (2005)

Download references


We thank A. Tsay, J. Du, H. Widlund, M. Seiberg, I. Davis and A. Wagner for discussions and help with technical aspects of the studies; I. Jackson for Dct-LacZ mice; S. Yuspa for PAM212 cells; and D. Bennett for Melan-C cells. We also thank the University of Kentucky's Teaching and Academic Support Center (TASC) for help with figure preparation. This work was supported by grants from the NIH (D.E.F.) and the Doris Duke Charitable Foundation. S.I. and K.W. were supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports and Technology of Japan. D.E.F. is the Jan and Charles Nirenberg Fellow in Pediatric Oncology at the Dana-Farber Cancer Institute, and a Doris Duke Distinguished Clinical Investigator.

Author information

Correspondence to David E. Fisher.

Ethics declarations

Competing interests

D.E.F. discloses a consulting/equity relationship with Magen BioSciences.

Supplementary information

Supplementary Figure 1

Untreated ears from C57BL/6 Dopachrome tautomerase (DCT)-LacZ transgenic (gift of Ian Jackson) mice were stained for β-galactosidase30 to identify melanocytes. (PDF 138 kb)

Supplementary Figure 2

Photographs and melanin quantification of C57BL/6 pigment variants used in this study. (PDF 101 kb)

Supplementary Figure 3

Forskolin-induced skin darkening of mc1re/e animals. (PDF 91 kb)

Supplementary Figure 4

a, Comparison of skin melanization induced by pure forskolin vs. C. forskohlii root extract. b, Thymine dimer formation in the skin of depillated animals treated as described in Figure 3 as detected by immunohistochemistry to control for the possibility that melanin deposition could interfere with fluorescence-based thymine dimer detection. c, Induction of melanin by topical forskolin treatment does not depend on presence of the K14-SCF transgene. (PDF 200 kb)

Supplementary Figure 5

a, Forskolin treatment (80 µmoles) prevented UV-induced weight loss. b, Photographs of vehicle-treated or forskolin-treated depillated animals after 16 weeks of UV exposure as indicated. (PDF 30 kb)

Supplementary Figure 6

Protective effect of topical forskolin against UV-induced skin pathology in nucleotide excision repair-deficient mice. (PDF 225 kb)

Supplementary Figure Legends

This file contains text to accompany the above Supplementary Figures. (DOC 39 kb)

Supplementary Methods

This file contains additional details of the methods used in this study. (DOC 81 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading

Figure 1: UV-induced tanning requires an intact MSH pathway.
Figure 2: Forskolin, but not UV, rescues eumelanin production in mice with defective MSH signalling.
Figure 3: Forskolin-induced melanin deposition protects against UV-mediated cutaneous damage.
Figure 4: Protective effect of topical forskolin against chronic UV damage.


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.