Review
MC1R and the response of melanocytes to ultraviolet radiation

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Abstract

The constitutive color of our skin plays a dramatic role in our photoprotection from solar ultraviolet radiation (UVR) that reaches the Earth and in minimizing DNA damage that gives rise to skin cancer. More than 120 genes have been identified and shown to regulate pigmentation, one of the key genes being melanocortin 1 receptor (MC1R) that encodes the melanocortin 1 receptor (MC1R), a seven-transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Modulation of MC1R function regulates melanin synthesis by melanocytes qualitatively and quantitatively. The MC1R is regulated by the physiological agonists α-melanocyte-stimulating hormone (αMSH) and adrenocorticotropic hormone (ACTH), and antagonist agouti signaling protein (ASP). Activation of the MC1R by binding of an agonist stimulates the synthesis of eumelanin primarily via activation of adenylate cyclase. The significance of cutaneous pigmentation lies in the photoprotective effect of melanin, particularly eumelanin, against sun-induced carcinogenesis. Epidermal melanocytes and keratinocytes respond to UVR by increasing their expression of αMSH and ACTH, which up-regulate the expression of MC1R, and consequently enhance the response of melanocytes to melanocortins. Constitutive skin pigmentation dramatically affects the incidence of skin cancer. The pigmentary phenotype characterized by red hair, fair complexion, inability to tan and tendency to freckle is an independent risk factor for all skin cancers, including melanoma. The MC1R gene is highly polymorphic in human populations, and allelic variation at this locus accounts, to a large extent, for the variation in pigmentary phenotypes and skin phototypes (SPT) in humans. Several allelic variants of the MC1R gene are associated with the red hair and fair skin (RHC) phenotype, and carrying one of these variants is thought to diminish the ability of the epidermis to respond to DNA damage elicited by UVR. The MC1R gene is considered a melanoma susceptibility gene, and its significance in determining the risk for skin cancer is of tremendous interest.

Section snippets

Solar ultraviolet radiation

The main etiological factor for skin cancer (basal and squamous cell carcinoma and melanoma) is sun exposure. Solar radiation that reaches the Earth is a complex physical entity that consists of a continuous spectrum of electromagnetic radiation that can be divided into three major regions: infrared (700–2000 nm) and visible (400–700 nm), which contribute equally to about 87% of total sunlight energy, and solar ultraviolet radiation (UVR) (200–400 nm), which comprises the remaining 13% [1].

In

Ozone

For over 50 years, chlorofluorocarbons (CFCs) were thought of as miracle substances. They are stable, non-flammable, low in toxicity and inexpensive to produce. Over time, CFCs found uses as refrigerants, solvents, foam blowing agents, and in many other smaller applications. Other chlorine-containing compounds include methyl chloroform, a solvent, and carbon tetrachloride, an industrial chemical. Halons, extremely effective fire-extinguishing agents, and methyl bromide, an effective produce and

Minimal erythemal dose (MED) and skin phototype

Careful studies of human skin [24] revealed no significant differences in the actual number of melanocytes. Instead, ethnic differences in skin color come mainly from differences in the rate at which melanosomes are produced and melanized in melanocytes, and then distributed and transferred to neighboring keratinocytes [25].

The concept of “sun reactive” skin typing was created in 1975 for a specific need: to be able to classify persons with “lightly pigmented skin” in order to select the

Photoprotective role of melanin

Melanin serves as a photoprotective agent against the damaging effects of UVR, as evidenced by an inverse correlation between the melanin content of human skin and the incidence of skin carcinomas and melanomas induced by UVR. In the US, rates of basal and squamous cell carcinomas are 50 times higher in Caucasians than in African–Americans [34], who show a 13-fold lower incidence of melanoma [35].

The exact chemical structures of the two types of melanin are still unknown, probably due to

The melanocortin receptors

One way to control skin pigmentation was elucidated at the beginning of the 1990s with the molecular characterization of the melanocyte-stimulating hormone receptor (MSHR) now named melanocortin 1-receptor (MC1R) and its antagonist agouti signal protein (ASP) [41], [42]. It has been known for many years that two loci, extension and agouti, were involved in the qualitative (eu- and phaeomelanin) and quantitative regulation of mammalian pigmentation [43], [44]. ASP was known to be produced in

Regulation of MC1R activity by its physiological agonists and antagonist

The significance of human cutaneous pigmentation lies in its protective role against sun-induced DNA damage and photocarcinogenesis [90], [91]. Total melanin content and the relative amounts of eumelanin and pheomelanin synthesized by human epidermal and follicular melanocytes are important determinants of skin and hair color, respectively [92], [93]. Stimulation of MC1R by αMSH and other POMC peptides induces an increase in intracellular cAMP and the synthesis of photoprotective eumelanin.

Human MC1R allelic variants: link to sun sensitivity and/or melanoma susceptibility

Human pigmentation is regulated by more than 120 genes [108], and among them, the MC1R is highly polymorphic, suggesting its significance in the wide range of human pigmentation patterns [40]. Today, MC1R is the only gene in which variations can explain differences in normal pigmentation in humans [109]. An effect of the MC1R gene on the variation in human pigmentation has been hypothesized since MC1R variants causing coat color changes are known in other mammalian species [110], [111], [112],

Response of melanocytes to UVR

We previously reported that exposure of cultured primary melanocytes to UVR induced a significant reduction in MC1R mRNA level [93]. This effect disappeared within 24 h after UV irradiation at relatively low doses, but persisted in NHM irradiated with a cytotoxic dose of UVR. The reversal of the effects of low or moderate doses of UVR might be attributed to stimulation of αMSH and ACTH production in NHM [139], [140], which is expected to up-regulate MC1R expression in a paracrine fashion. We

Response of MC1R to UV/αMSH with respect to the various genotypes/phenotypes

More than 30 allelic variants of the human MC1R have been identified, mainly in Northern European populations and in Australia [115], [116], [120], [153]. As noted above, among the variants so far reported, R142H, R151C, R160W and D294H are the mutations mostly associated with red hair phenotype and reduced tanning ability [116], [118], [120], [154]. These four MC1R variants are common in melanoma patients, and increase the risk of melanoma by more than two-fold [121]. Homozygote or compound

Indirect effects

Interestingly, UV has been shown to increase POMC production by keratinocytes [156]. It should be mentioned that in human epidermis the major POMC peptide seems to be ACTH [144], which is actually more efficient at activating MC1R than are the various forms of αMSH. Additionally, studies on murine melanoma cells have demonstrated that UVB radiation up-regulates the expression of MC1R [157]. Very recently, it has been shown that UV down-regulates the expression of neprilysine, a peptidase that

Melanocyte survival

In vitro, melanocytes respond to UV with dose-dependent growth arrest and reduction in survival [143], [155], [166]. Melanocytes have low proliferation capacity and it is reasonable to assume that due to their significance in photoprotection of the skin, mechanisms were selected insuring melanocyte survival. In fact, melanocytes are thought to resist apoptosis by constitutive expression of the anti-apoptotic protein Bcl2.

Many of the effects of UV on human skin are indirectly mediated by

UV-induced DNA damage

The most drastic effects of UV exposure are photoaging and photocarcinogenesis. Melanin guards against the photodamaging effects of UV by acting as a filter that limits the penetration of UV rays through the epidermis [90], [91]. Melanin also acts as a scavenger of UV-induced reactive oxygen species that cause lipid peroxidation and damage proteins and DNA [179]. Acute exposure of the skin to solar UV results in extensive DNA damage, leading to apoptosis, which is best evidenced by the

UVR induces local and systemic immunosuppression

UVB radiation is among the most ubiquitous agents in the environment, and humans are invariably exposed to it. UVR not only initiates and promotes the transformation of normal epidermal cells to cancer cells via dysregulation of intracellular signaling pathways and via its mutagenic effects on cellular DNA, but also by altering the host immunity by reducing its capability for surveillance against tumor or viral antigens. Since UVB radiation is almost completely absorbed within the epidermis,

Anti-inflammatory effect of αMSH, role of MC1R?

αMSH is one mediator capable of counteracting inflammation. MC1R, first demonstrated in melanoma tumor cell lines [201], is present on immunologically important cells such as macrophages, monocytes, dendritic cells and neutrophils [202], [203], [204], [205].

MC1R expression has been shown to be up-regulated not only in melanocytes, but also in monocytes in response to external stimuli such as UVB-radiation and retinoic acid [206]. Support for the anti-inflammatory effects of αMSH is found in

Concluding remarks

Cancer of the skin is the most common of all cancers. Melanoma accounts for about 4% of skin cancer cases, but it causes about 79% of skin cancer deaths. The number of new cases of melanoma in the United States is on the rise. The American Cancer Society estimates that in 2004 there will be 64,200 new cases of melanoma in this country and that about 8600 people will die of this disease. Australia, Northern European and other countries are also paying a huge price to skin cancer. There is an

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