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)-alpha-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.
Highlights
Human pigmentation is a polygenic trait with Ͼ60 genetic loci identified so far [5, 6]
Differentiating melanocytes were grown on coverslips for 3 days prior to UV irradiation experiments, and cells were transfected with siRNA reagents 24 h prior to UV irradiation. siRNA reagents were transfected into cells using Lipofectamine 2000 according to the manufacturer’s recommendation to a final concentration of 50 nM. siRNA reagents were: negative control (Ambion), NR4A1 (1:1 pooled ID41824 and ID41752; Ambion), and NR4A2 (Smartpool; Dharmacon)
NR4A1 and NR4A2 showed maximal induction at 1 h, while maximal induction of NR4A3 occurred at 2 h post NDP-MSH treatment
Summary
Human pigmentation is a polygenic trait with Ͼ60 genetic loci identified so far [5, 6]. Molecular analysis has revealed that MC1R signaling modulates the expression and function of the microphthalmia-associated transcription factor, a key regulator of pigmentation genes, suggesting that this pathway underlies MC1R coordination of melanogenesis [16]. We report that all three NR4A receptors are induced and function immediately downstream of MC1R signaling in melanocytic cells. We demonstrate the impaired induction of the NR4A gene family in primary human melanocytes of MC1R variant genotype. This observation reveals the NR4A gene family as one of the immediate transcriptional targets of MC1R signaling in melanocytic cells. The functional role of this nuclear receptor subfamily in melanocyte gene expression remains to be explored
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