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

doi:10.1038/nature05098

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 journal › Article › peer-review

278 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 Mc1r^e/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 language	English
Pages (from-to)	340-344
Number of pages	5
Journal	Nature
Volume	443
Issue number	7109
DOIs	https://doi.org/10.1038/nature05098
State	Published - 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.

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General

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10.1038/nature05098

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@article{3eedf2c2f6574879bd521fea8320e2ee,

title = "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). 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.",

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

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{\textquoteright}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.",

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doi = "10.1038/nature05098",

language = "English",

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T1 - Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning

AU - D'Orazio, John A.

AU - Nobuhisa, Tetsuji

AU - Cui, Rutao

AU - Arya, Michelle

AU - Spry, Malinda

AU - Wakamatsu, Kazumasa

AU - Igras, Vivien

AU - Kunisada, Takahiro

AU - Granter, Scott R.

AU - Nishimura, Emi K.

AU - Ito, Shosuke

AU - Fisher, David E.

N1 - 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.

PY - 2006/9/21

Y1 - 2006/9/21

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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