Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells
Copyright policy )Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells
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.
- University of Queensland Australia
- University of Queensland Australia
- University of Queensland Australia
Receptors, Steroid, DNA Repair, Receptors, Cytoplasmic and Nuclear, 612, Dna-damage, Mice, C1, Cell Line, Tumor, Ngfi-B, Nuclear Receptor Subfamily 4, Group A, Member 1, Animals, Humans, Melanoma-cells, Alleles, Skeletal-muscle, Stimulating Hormone, Ultraviolet-radiation, Red Hair, Receptor Cross-Talk, 060111 Signal Transduction, Human Pigmentation, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Skin-cancer Risk, Mutation, Melanocytes, MC1R Variant Alleles, 060405 Gene Expression (incl. Microarray and other genome-wide approaches), Receptor, Melanocortin, Type 1, Signal Transduction, Transcription Factors
Receptors, Steroid, DNA Repair, Receptors, Cytoplasmic and Nuclear, 612, Dna-damage, Mice, C1, Cell Line, Tumor, Ngfi-B, Nuclear Receptor Subfamily 4, Group A, Member 1, Animals, Humans, Melanoma-cells, Alleles, Skeletal-muscle, Stimulating Hormone, Ultraviolet-radiation, Red Hair, Receptor Cross-Talk, 060111 Signal Transduction, Human Pigmentation, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Skin-cancer Risk, Mutation, Melanocytes, MC1R Variant Alleles, 060405 Gene Expression (incl. Microarray and other genome-wide approaches), Receptor, Melanocortin, Type 1, Signal Transduction, Transcription Factors
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