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). 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.
D'Orazio
John A
JA
Melanoma Program, Dana-Farber Cancer Institute & Children's Hospital, 44 Binney Street, Boston, Massachusetts 02115, USA.
Nobuhisa
Tetsuji
T
Cui
Rutao
R
Arya
Michelle
M
Spry
Malinda
M
Wakamatsu
Kazumasa
K
Igras
Vivien
V
Kunisada
Takahiro
T
Granter
Scott R
SR
Nishimura
Emi K
EK
Ito
Shosuke
S
Fisher
David E
DE
D000287:Administration, Topical; D000818:Animals; D005576:Colforsin / Q000008:administration & dosage* / Q000494:pharmacology*; D008543:Melanins / Q000096:biosynthesis; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D044102:Receptor, Melanocortin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D012871:Skin Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012880:Skin Pigmentation / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D014466:Ultraviolet Rays
D008543:Melanins; D044102:Receptor, Melanocortin, Type 1; C041877:eumelanin; D005576:Colforsin; D009074:Melanocyte-Stimulating Hormones