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

John A. D'Orazio, Tetsuji Nobuhisa, Rutao Cui, Michelle Arya, Malinda Spry, Kazumasa Wakamatsu, Vivien Igras, Takahiro Kunisada, Scott R. Granter, Emi K. Nishimura, Shosuke Ito, David E. Fisher

Research output: Contribution to journalArticlepeer-review

269 Scopus citations

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). 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.

Original languageEnglish
Pages (from-to)340-344
Number of pages5
JournalNature
Volume443
Issue number7109
DOIs
StatePublished - Sep 21 2006

Bibliographical note

Funding Information:
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.

ASJC Scopus subject areas

  • General

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