Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells

doi:10.1074/jbc.M800480200

Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells^*

Division of Molecular Genetics and Development, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia

2 To whom correspondence may be addressed. E-mail: a.smith{at}imb.uq.edu.au.
3 A Senior Research Fellow of the NHMRC. To whom correspondence may be addressed. E-mail: r.sturm{at}imb.uq.edu.au.
4 A Professorial Research Fellow of the NHMRC. To whom correspondence may be addressed: Inst. for Molecular Bioscience, Carmody Rd., University of Queensland, St. Lucia, Australia 4072. Fax: 61-7-33462101; E-mail: g.muscat{at}imb.uq.edu.au.

Abstract

The melanocortin-1 receptor (MCIR) is a G-protein-coupled receptor expressed primarily in melanocytes and is known to play a pivotal role in the regulation of pigmentation in mammals. In humans MC1R has been found to be highly polymorphic with several functional variants associated with the phenotype of red hair color and fair skin, cutaneous UV sensitivity, and increased risk of developing melanoma and non-melanoma skin cancer. Recent evidence suggests that MC1R plays a photo-protective role in melanocytes in response to UV irradiation. Relatively few genetic targets of MC1R signaling have been identified independent of the pigmentation pathway. Here we show that MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. Furthermore, primary human melanocytes harboring homozygous RHC variant MC1R alleles exhibited an impaired induction of NR4A genes in response to the potent MC1R agonist (Nle4,D-Phe7)-α-melanocyte-stimulating hormone. Using small interference RNA-mediated attenuation of NR4A1 and NR4A2 expression in melanocytes, the ability to remove cyclobutane pyrimidine dimers following UV irradiation appeared to be impaired in the context of MC1R signaling. These data identify the NR4A receptor family as potential mediators of an MC1R-coordinated DNA damage response to UV exposure in melanocytic cells.

Footnotes

↵⁵ The abbreviations used are: MC1R, melanocortin-1 receptor; α-MSH, α-melanocyte-stimulating hormone; NDP-MSH, (Nle4,D-Phe7)-α-MSH; NR, nuclear receptor; q-RT-PCR, quantitative real-time PCR; RHC, red hair color; UVB, ultraviolet-B radiation; MAPK, mitogen-activated protein kinase; MEK, MAPK/extracellular signal-regulated kinase kinase; siRNA, small interference RNA; EMSA, electrophoretic mobility shift assay; WT, wild type; CPD, cyclobutane pyrimidine.
↵^* This work was supported by National Health and Medical Research Council of Australia (NHMRC) Project Grant 455839 and Queensland Cancer Council Grant 511110. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ Both authors contributed equally to this work.
- Received January 18, 2008.
- Revision received February 21, 2008.
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