Melanocortin-1 receptor signaling markedly induces the expression of the NR4A nuclear receptor subgroup in melanocytic cells
Open accessAbstract
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.
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α-MSH reduces the generation of UV-induced DNA photoproducts by enhancing nucleotide excision repair and diminishes the induction of oxidative DNA injury through elimination of ROS.
“For example, α-MSH is known to reduce the generation of UV-induced DNA photoproducts by enhancing nucleotide excision repair (NER) and to diminish the induction of oxidative DNA injury through elimination of ROS [77,78].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [77]
The results section reports that NDP-MSH-treated human melanocytes cleared more UVB-induced cyclobutane pyrimidine dimers than vehicle-treated cells. The paper supports enhanced clearance of these DNA lesions, but does not establish reduced initial photoproduct generation, identify nucleotide excision repair as the mechanism, or report elimination of ROS and reduced oxidative DNA injury. (LLM, conf=0.86)
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Cites
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MC1R and the response of melanocytes to ultraviolet radiation
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Molecular Regulation of <scp>UV</scp> ‐Induced <scp>DNA</scp> Repair
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Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease
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Melanocortin MC1 receptor in human genetics and model systems
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Retracted
- Authors
- Smith, A. G., Luk, N., Newton, R. A., Roberts, D. W., Sturm, R. A., & Muscat, G. E. O.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- Smith, Aaron G.
- Sturm, Richard A.
- Muscat, George E.O.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 283
- Issue
- 18
- Pages
- 12564-12570
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2004010426
- Cited by
- 98
- References
- 2
- Citations by year
- 2025: 3 · 2024: 3 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 4 · 2017: 7 · 2016: 6 · 2015: 4 · 2014: 10 · 2013: 6 · 2012: 8
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council (455839)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- MC1R, NR4A nuclear receptors, melanocytes, melanoma cells, G protein-coupled receptor signaling, DNA damage response, melanogenesis, transcriptional regulation
- MeSH terms
- Alleles, Animals, DNA Repair, DNA-Binding Proteins, Humans, Melanocytes, Mutation, Receptors, Steroid, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Receptors, Cytoplasmic and Nuclear, Receptor Cross-Talk, Receptor, Melanocortin, Type 1, Cell Line, Tumor, Mice, Nuclear Receptor Subfamily 4, Group A, Member 1
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