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

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

Correspondence to David E. Fisher.

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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)

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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.

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