Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix

Robinson, Samantha J.; Healy, Eugene

doi:10.1038/sj.onc.1205913

Cited by 57 publications

(45 citation statements)

References 60 publications

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“…However, not all studies are in agreement (Ichii-Jones et al, 1998). a-Melanocyte-simulating hormone has been demonstrated to affect melanoma growth and attachment to ECM proteins in cells with wild-type MC-1, but not in cells transfected with polymorphic variants (Robinson and Healy, 2002). The current study provides strong evidence to suggest that two out of three human cell lines that possessed MC-1R polymorphisms, which gave a loss of cAMP response to MSH, resulted in cells that failed to respond to MSH with any reduction of invasion or protection against proinflammatory cytokine attack.…”

Section: Discussionmentioning

confidence: 99%

“…We also found a-MSH to reduce TNF-astimulated NF-kB activity (and oxidative stress) in keratinocyte and melanoma lines (Haycock et al, 1999(Haycock et al, , 2000, suggesting protection of the epidermis from inflammatory and oxidative stresses. In addition, B16 melanoma cells respond to a-MSH with inhibition of growth and reduced adhesion (Robinson and Healy, 2002).…”

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confidence: 99%

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Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

et al. 2003

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a-Melanocyte stimulating hormone (a-MSH) is known to have pleiotrophic functions including pigmentary, anti-inflammatory, antipyretic and immunoregulatory roles in the mammalian body. It is also reported to influence melanoma invasion with levels of a-, b-and g-MSH correlated clinically with malignant melanoma development, but other studies suggest a-MSH acts to retard invasion. In the present study, we investigated the action of a-MSH on three human melanoma cell lines (HBL, A375-SM and C8161) differing in metastatic potential. a-melanocyte-simulating hormone reduced invasion through fibronectin and also through a human reconstructed skin composite model for the HBL line, and inhibited proinflammatory cytokine-stimulated activation of the NF-kB transcription factor. However, A375-SM and C8161 cells did not respond to a-MSH. Immunofluorescent microscopy and Western blotting identified melanocortin-1 receptor (MC-1R) expression for all three lines and MC-2R on HBL and A375-SM lines. Receptor binding identified a similar affinity for a-MSH for all three lines with the highest number of binding sites on HBL cells. Only the HBL melanoma line demonstrated a detectable cyclic adenosine monophosphate (cAMP) response to a-MSH, although all three lines responded to acute a-MSH addition ( þ (À)-N 6 -(2-phenylisopropyl)-adenosine (PIA)) with an elevation in intracellular calcium. The nonresponsive lines displayed MC-1R polymorphisms (C8161, Arg (wt) 151/Cys 151; A375-SM, homozygous Cys 151), whereas the HBL line was wild type. Stable transfection of the C8161 line with wild-type MC-1R produced cells whose invasion was significantly inhibited by a-MSH. From this data, we conclude that a-MSH can reduce melanoma cell invasion and protect cells against proinflammatory cytokine attack in cells with the wild-type receptor (HBL).

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

et al. 2003

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“…Case control, kindred and population studies have demonstrated that, in general, two variant MC1R alleles result in red hair whereas a single variant allele gives rise to fairer skin type (17)(18)(19)(20)(21)(22). Cell transfection assays and transgenic mouse work have indicated that a number of the variant receptors, in particular the Arg151Cys, Arg160Trp, and Asp294His variants, which are frequently associated with red hair and fair skin, are significantly functionally compromised in their ability to signal intracellularly via cAMP, leading to a lighter/phaeomelanic pigmentation phenotype (23)(24)(25). It is therefore possible that human MC1R variants could have consequences on the anti-inflammatory and/or immunomodulatory actions of ␣MSH in humans, especially in cases where the monocyte/macrophage plays an important role.…”

Section: ␣-Melanocyte-stimulating Hormone Suppresses Antigen-induced mentioning

confidence: 99%

“…MC1R is also expressed by melanocytes in the skin, where it plays a central role in human pigmentation. MC1R variants have profound effects on human pigmentation, causing red hair and fair skin phenotypes as a result of the significantly reduced ability of variant receptors to signal via cAMP (18,20,(22)(23)(24)(25). To investigate whether variability in ␣MSH-induced suppression of SK/SD-induced lymphocyte proliferation between subjects was due to genetic variability at the MC1R locus, we extended the study population to include a total of 26 subjects.…”

Section: Suppression Of Sk/sd-induced Lymphocyte Proliferation Is Unrmentioning

confidence: 99%

α-Melanocyte-Stimulating Hormone Suppresses Antigen-Induced Lymphocyte Proliferation in Humans Independently of Melanocortin 1 Receptor Gene Status

Cooper

Robinson

Pickard

et al. 2005

The Journal of Immunology

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Studies in mice indicate that α-melanocyte-stimulating hormone (αMSH) is immunosuppressive, but it is not known whether αMSH suppresses human immune responses to exogenous Ags. Human PBMCs, including monocytes, express the melanocortin 1 receptor (MC1R), and it is thought that the ability of αMSH to alter monocyte-costimulatory molecule expression and IL-10 release is mediated by this receptor. However, the MC1R gene is polymorphic, and certain MC1R variants compromise receptor signaling via cAMP, resulting in red hair and fair skin. Here, we have investigated whether αMSH can suppress Ag-induced lymphocyte proliferation in humans and whether these effects are dependent on MC1R genotype. αMSH suppressed streptokinase-streptodornase-induced lymphocyte proliferation, with maximal inhibition at 10−13–10−11 M αMSH. Anti-IL-10 Abs failed to prevent suppression by αMSH, indicating that it was not due to MC1R-mediated IL-10 release by monocytes. Despite variability in the degree of suppression between subjects, similar degrees of αMSH-induced immunosuppression were seen in individuals with wild-type, heterozygous variant, and homozygous/compound heterozygous variant MC1R alleles. RT-PCR of streptokinase-streptodornase-stimulated PBMCs for all five melanocortin receptors demonstrated MC1R expression by monocytes/macrophages, MC1R and MC3R expression by B lymphocytes, but no melanocortin receptor expression by T lymphocytes. In addition, αMSH did not significantly inhibit anti-CD3 Ab-induced lymphocyte proliferation, whereas αMSH and related analogs (SHU9119 and MTII) inhibited Ag-induced lymphocyte proliferation in monocyte-depleted and B lymphocyte-depleted assays. These findings demonstrate that αMSH, acting probably via MC1R on monocytes and B lymphocytes, and possibly also via MC3R on B lymphocytes, has immunosuppressive effects in humans but that suppression of Ag-induced lymphocyte proliferation by αMSH is independent of MC1R gene status.

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“…Because skin pigmentation is primarily regulated by the MC1R, its gene is considered a susceptibility gene for melanoma (40).…”

Section: Role Of Melanin In Photoprotection Of the Skinmentioning

confidence: 99%

The Regulation of Skin Pigmentation

Yamaguchi

Brenner

Hearing

2007

Journal of Biological Chemistry

412

344

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Visible pigmentation of the skin, hair, and eyes depends primarily on the functions of melanocytes, a very minor population of cells that specialize in the synthesis and distribution of the pigmented biopolymer melanin. Melanocytes are derived from precursor cells (called melanoblasts) during embryological development, and melanoblasts destined for the skin originate from the neural crest. The accurate migration, distribution, and functioning of melanoblasts/melanocytes determine the visible phenotype of organisms ranging from simple fungi to the most complex animal species. In human skin, melanocytes are localized at the dermal/epidermal border in a characteristic regularly dispersed pattern. Each melanocyte at the basal layer of the epidermis is functionally connected to underlying fibroblasts in the dermis and to keratinocytes in the overlying epidermis. Those three types of cells are highly interactive and communicate with each other via secreted factors and their receptors and via cell/cell contacts to regulate the function and phenotype of the skin. Overview: Architecture of the SkinEpidermal melanocytes occur at an approximate ratio of 1:10 among basal keratinocytes and distribute the melanin they produce to ϳ40 overlying suprabasal keratinocytes via their elongated dendrites and cell/cell contacts (presented schematically in Fig. 1). Although melanocytes and stem cell keratinocytes in the basal layer of the epidermis are very stable populations that proliferate extremely slowly under normal circumstances, keratinocytes in the upper layers of the epidermis proliferate relatively rapidly. That upward pressure carries them toward the surface of the skin along with their ingested melanin to form a critical barrier for the organism against the environment and the many stresses that originate there. Thus it is not the melanin within melanocytes only, but in combination with the pigment in more superficial layers, that gives skin its characteristic color. Although melanocytes in other locations of the body (e.g. hair follicles, eyes, inner ear, etc.) interact with surrounding cells in manners distinct from those in the epidermis, the basic processes involved in producing the melanin and the organelles within which it is synthesized (termed melanosomes) are comparable, as are the factors that regulate melanogenesis. This review will restrict itself to epidermal pigmentation, and readers interested in factors influencing pigmentation at other sites should consult recent reviews (1-6) and books (7, 8) on those topics.

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Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix

Cited by 57 publications

References 60 publications

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

α-Melanocyte-Stimulating Hormone Suppresses Antigen-Induced Lymphocyte Proliferation in Humans Independently of Melanocortin 1 Receptor Gene Status

The Regulation of Skin Pigmentation

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