Melanocortin 1 receptor genotype: An important determinant of the damage response of melanocytes to ultraviolet radiation

Ana Luisa Kadekaro, Sancy Leachman, Renny J. Kavanagh, Viki Swope, Pamela Cassidy, Dorothy Supp, Maureen Sartor, Sandy Schwemberger, George Babcock, Kazumasa Wakamatsu, Shosuke Ito, Amy Koshoffer, Raymond E. Boissy, Prashiela Manga, Richard A. Sturm, Zalfa A. Abdel-Malek

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to α-melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.

Original languageEnglish (US)
Pages (from-to)3850-3860
Number of pages11
JournalFASEB Journal
Volume24
Issue number10
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

Receptor, Melanocortin, Type 1
Melanocortins
Melanocytes
Ultraviolet radiation
Genotype
Radiation
Melanoma
Genes
DNA Repair
Repair
Melanocortin Receptors
Hair Color
Genomic Instability
DNA
Radiation Effects
Pigmentation
Microarrays
Hair
Hydrogen Peroxide
Antioxidants

Keywords

  • cAMP pathway
  • DNA repair
  • MC1R variants
  • Melanoma susceptibility

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Melanocortin 1 receptor genotype : An important determinant of the damage response of melanocytes to ultraviolet radiation. / Kadekaro, Ana Luisa; Leachman, Sancy; Kavanagh, Renny J.; Swope, Viki; Cassidy, Pamela; Supp, Dorothy; Sartor, Maureen; Schwemberger, Sandy; Babcock, George; Wakamatsu, Kazumasa; Ito, Shosuke; Koshoffer, Amy; Boissy, Raymond E.; Manga, Prashiela; Sturm, Richard A.; Abdel-Malek, Zalfa A.

In: FASEB Journal, Vol. 24, No. 10, 2010, p. 3850-3860.

Research output: Contribution to journalArticle

Kadekaro, AL, Leachman, S, Kavanagh, RJ, Swope, V, Cassidy, P, Supp, D, Sartor, M, Schwemberger, S, Babcock, G, Wakamatsu, K, Ito, S, Koshoffer, A, Boissy, RE, Manga, P, Sturm, RA & Abdel-Malek, ZA 2010, 'Melanocortin 1 receptor genotype: An important determinant of the damage response of melanocytes to ultraviolet radiation', FASEB Journal, vol. 24, no. 10, pp. 3850-3860. https://doi.org/10.1096/fj.10-158485
Kadekaro, Ana Luisa ; Leachman, Sancy ; Kavanagh, Renny J. ; Swope, Viki ; Cassidy, Pamela ; Supp, Dorothy ; Sartor, Maureen ; Schwemberger, Sandy ; Babcock, George ; Wakamatsu, Kazumasa ; Ito, Shosuke ; Koshoffer, Amy ; Boissy, Raymond E. ; Manga, Prashiela ; Sturm, Richard A. ; Abdel-Malek, Zalfa A. / Melanocortin 1 receptor genotype : An important determinant of the damage response of melanocytes to ultraviolet radiation. In: FASEB Journal. 2010 ; Vol. 24, No. 10. pp. 3850-3860.
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AB - The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to α-melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.

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