Quantitative analysis of MC1R gene expression in human skin cell cultures

Roberts, Donna; Newton, R.; Beaumont, Kimberley A.; Leonard, J. Helen; Sturm, Richard A.

doi:10.1111/j.1600-0749.2005.00286.x

Cited by 85 publications

(94 citation statements)

References 106 publications

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“…The HA-hMC1R migrated at a lower molecular mass than predicted. Previously, FLAG-tagged hMC1R was observed to migrate at a lower molecular mass than untagged hMC1R (Sanchez Mas et al 2002, Roberts et al 2006, Sanchez-Laorden et al 2006. Epitope tagging the hMC1R may alter hMC1R conformation resulting in greater mobility on SDS-PAGE.…”

Section: Discussionmentioning

confidence: 99%

hMRAPa specifically alters hMC4R molecular mass and N-linked complex glycosylation in HEK293 cells

Kay¹,

Botha²,

Montgomery³

et al. 2013

Journal of Molecular Endocrinology

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Human melanocortin 2 receptor accessory protein 1(hMRAPa) is essential for human melanocortin 2 receptor (hMC2R)-regulated adrenal steroidogenesis. hMRAPa enhances hMC2R N-linked glycosylation and maturation, promotes hMC2R cell surface expression and enables ACTH to bind and activate the MC2R. However, hMRAPa is predicted to have functions beyond its critical role in hMC2R activity. It is more widely expressed than the hMC2R and it has been shown to co-immunoprecipitate with all other hMCR subtypes and other G-protein-coupled receptors, when these are co-expressed with each receptor in heterologous cells. The physiological relevance of hMRAPa interactions with these receptors is unknown. We hypothesised that hMRAPa could influence post-translational processing and maturation of these receptors, similar to its actions on the hMC2R. Here we used co-immunoprecipitation and western blotting techniques to characterise effects of hMRAPa-FLAG co-expression on the maturation of each HA-tagged hMCR subtype and the HA-tagged human calcitonin receptor-like receptor (hCL), co-expressed in HEK293 cells. While hMRAPa-FLAG interacted with all five HA-hMCR subtypes and the HA-hCL, it only altered HA-hMC4R molecular mass. This altered HA-hMC4R molecular mass was due to a change in endoglycosidase H-resistant complex N-linked glycosylation, which we observed for HA-hMC4R in both intracellular and cell surface fractions. This effect was specific to the HA-hMC4R as hMRAPa did not alter the molecular mass of any of the other receptors that we examined. In conclusion, the specific effects of hMRAPa on hMC4R molecular mass and complex N-linked glycosylation provide evidence in support of a role for MRAPa in hMC4R functions.

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Section: Discussionmentioning

confidence: 99%

hMRAPa specifically alters hMC4R molecular mass and N-linked complex glycosylation in HEK293 cells

Kay¹,

Botha²,

Montgomery³

et al. 2013

Journal of Molecular Endocrinology

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“…The immune and inflammatory responses to UV exposure are at least partially mediated via the MC1R gene. [40][41][42] It has been reported that a-MSH, the MC1R ligand, can also suppress melanoma cell proliferation and reduce the adhesion of melanoma cell to extracellular matrix. 43,44 The MC1R variants failed to exert these effects in the response to a-MSH in transfection assays.…”

Section: Discussionmentioning

confidence: 99%

Melanocortin 1 receptor variants and skin cancer risk

Han

Kraft

Colditz

et al. 2006

Intl Journal of Cancer

124

145

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Melanocortin 1 receptor (MC1R) gene variants are associated with red hair and fair skin color. We assessed the associations of common MC1R genotypes with the risks of 3 types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 873 controls). We found that the 151Cys, 160Trp and 294His variants were significantly associated with red hair, fair skin color and childhood tanning tendency. The MC1R variants, especially the 151Cys variant, were associated with increased risks of the 3 types of skin cancer, after controlling for hair color, skin color and other skin cancer risk factors. Carriers of the 151Cys variant had an OR of 1.65 (95% CI, 1.04-2.59) for melanoma, 1.67 (1.12-2.49) for SCC and 1.56 (1.03-2.34) for BCC. Women with medium or olive skin color carrying 1 nonred hair color allele and 1 red hair color allele had the highest risk of melanoma. A similar interaction pattern was observed for red hair and carrying at least 1 red hair color allele on melanoma risk. We also observed that the 151Cys variant contributed additional melanoma risk among red-haired women. The information on MC1R status modestly improved the risk prediction; the increase was significant for melanoma and BCC (p, 0.004 and 0.05, respectively). These findings indicated that the effects of the MC1R variants on skin cancer risk were independent from self-reported phenotypic pigmentation. ' 2006 Wiley-Liss, Inc.

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“…34 The expression of MC1R in cells other than melanocytes is reported to be much lower with unclear functional relevance. 36,37 However, the reported association of the variants in the gene with l-opioid analgesia in humans and mice provided evidence for its expression and function in cells other than melanocytes. 38 The synthesis of melanocortins in skin is reported to enhance DNA repair, preserve melanocyte survival and stimulate melanogenesis to provide optimal photoprotection mediated via MC1R.…”

Section: Discussionmentioning

confidence: 99%

MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

Scherer

Bermejo

Rudnai

et al. 2007

Intl Journal of Cancer

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The variants within the human melanocortin 1 receptor (MC1R) gene are associated with an increased risk of different skin cancers. In this study, we genotyped by direct sequencing, 529 cases of basal cell carcinoma of the skin (BCC) and 533 healthy controls for polymorphisms in the entire MC1R gene. In addition to 10 common polymorphisms, we detected 23 rare variants in the gene. The presence of any nonsynonymous MC1R variant was associated with an increased risk in the carriers (odds ratio OR 1.66, 95% confidence interval CI 1.28-2.14) corresponding to a population attributable fraction of about 27%. The odds ratio for the risk in the carriers of 2 MC1R variants was 2.69 (95% CI 1.77-4.08). The risk of BCC in the carriers of MC1R variants with fair complexion was almost twice as much as in the corresponding noncarriers. The carriers of the R163Q variant with a medium skin complexion were at a 3-fold higher risk than the noncarrier counterparts. The interaction, of effect on the BCC risk, between the MC1R variants and types of skin response to sun exposure was greater than multiplicative. We also observed a multiplicative interaction of risk due to the MC1R variants and the common allele (high risk) of the T241M polymorphism in the XRCC3 gene. Our data confirmed the status of the nonsynonymous MC1R variants as independent genetic risk factors for BCC. However, the mechanism through which the variants influence the risk likely involves complex interactions with other genetic and host risk factors. ' 2007 Wiley-Liss, Inc.Key words: MC1R; polymorphisms; basal cell carcinoma; complexion; interactions Skin pigmentation and DNA repair constitute intrinsic mechanisms evolved to prevent skin carcinogenesis. 1,2 Skin pigmentation, which inhibits DNA damage, manifests a preventive and DNA repair a corrective mechanism. A number of genes involved both in DNA repair and pigmentation, contingent to environmental and other historical selection constraints, are highly polymorphic. [3][4][5] Many of the polymorphisms in the genes involved in these processes, as a corollary, modulate the risk and contribute to the inter-individual differences in susceptibility to the skin cancers including basal cell carcinoma of skin (BCC). [6][7][8][9] The G-protein coupled Melanocortin receptor 1 (MC1R) is a pivotal component in the pathway involved in the production of melanin in melanocytes. 10 Activation of MC1R by a-MSH (a-melanocyte-stimulating hormone) leads to increased cellular cAMP. The levels of cAMP, through tyrosinase, control the switch over of synthesis from pheomelanin to photo protective eumelanin. 11 The gene encoding MC1R is highly polymorphic and many variants are associated with an increased risk of skin cancers. 12,13 More than 60 nonconservative variants of the receptor are known and at least 3 frequent variants are strongly associated with high risk phenotypes of red hair and fair skin (RHC alleles; R151C, R160W and D294H) in Caucasians. [14][15][16] Several studies have reported association between variants in the MC1R...

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Quantitative analysis of MC1R gene expression in human skin cell cultures

Cited by 85 publications

References 106 publications

hMRAPa specifically alters hMC4R molecular mass and N-linked complex glycosylation in HEK293 cells

hMRAPa specifically alters hMC4R molecular mass and N-linked complex glycosylation in HEK293 cells

Melanocortin 1 receptor variants and skin cancer risk

MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

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