Letter | Published:

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

Nature 443, 340–344 (21 September 2006) | Download Citation

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Abstract

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.

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Acknowledgements

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

Affiliations

  1. Melanoma Program and

    • John A. D'Orazio
    • , Tetsuji Nobuhisa
    • , Rutao Cui
    • , Michelle Arya
    • , Vivien Igras
    • , Scott R. Granter
    • , Emi K. Nishimura
    •  & David E. Fisher

  2. Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute & Children's Hospital, 44 Binney Street, Boston, Massachusetts 02115, USA

    • John A. D'Orazio
    • , Tetsuji Nobuhisa
    • , Rutao Cui
    • , Michelle Arya
    • , Vivien Igras
    • , Emi K. Nishimura
    •  & David E. Fisher

  3. Department of Pediatrics, Markey Cancer Center and the Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA

    • John A. D'Orazio
    •  & Malinda Spry

  4. Department of Chemistry, Fujita Health University, School of Health Sciences, Toyoake, Aichi 470-1192, Japan

    • Kazumasa Wakamatsu
    •  & Shosuke Ito

  5. Department of Tissue and Organ Development, Gifu University, Graduate School of Medicine, 1-1 Yanagido, Gifu 501, Japan

    • Takahiro Kunisada

  6. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA

    • Scott R. Granter

  7. Department of Stem Cell Medicine, Kanazawa University, Cancer Research Institute, 13-1 Takaramachi, Kanazawa 920-0934, Japan

    • Emi K. Nishimura

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Competing interests

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

Corresponding author

Correspondence to David E. Fisher.

Supplementary information

PDF files

  1. 1.

    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.

  2. 2.

    Supplementary Figure 2

    Photographs and melanin quantification of C57BL/6 pigment variants used in this study.

  3. 3.

    Supplementary Figure 3

    Forskolin-induced skin darkening of mc1re/e animals.

  4. 4.

    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.

  5. 5.

    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.

  6. 6.

    Supplementary Figure 6

    Protective effect of topical forskolin against UV-induced skin pathology in nucleotide excision repair-deficient mice.

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  1. 1.

    Supplementary Figure Legends

    This file contains text to accompany the above Supplementary Figures.

  2. 2.

    Supplementary Methods

    This file contains additional details of the methods used in this study.

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DOI

https://doi.org/10.1038/nature05098

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