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 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.
authors.affiliation: Melanoma Program, Dana-Farber Cancer Institute & Children's Hospital, 44 Binney Street, Boston, Massachusetts 02115, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: D'Orazio
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Nobuhisa
authors.forename: Rutao
authors.initials: R
authors.lastname: Cui
authors.forename: Michelle
authors.initials: M
authors.lastname: Arya
authors.forename: Malinda
authors.initials: M
authors.lastname: Spry
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
authors.forename: Vivien
authors.initials: V
authors.lastname: Igras
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
authors.forename: Scott R
authors.initials: SR
authors.lastname: Granter
authors.forename: Emi K
authors.initials: EK
authors.lastname: Nishimura
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: 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
chemical_list: D008543:Melanins; D044102:Receptor, Melanocortin, Type 1; C041877:eumelanin; D005576:Colforsin; D009074:Melanocyte-Stimulating Hormones