Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 715
Filtrar
1.
PLoS One ; 15(8): e0235426, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817695

RESUMO

Coat colour is one of the most important economic traits of sheep and is mainly used for breed identification and characterization. This trait is determined by the biochemical function, availability and distribution of phaeomelanin and eumelanin pigments. In our study, we conducted a genome-wide association study to identify candidate genes and genetic variants associated with coat colour in 75 Chinese Tan sheep using the ovine 600K SNP BeadChip. Accordingly, we identified two significant SNPs (rs409651063 at 14.232 Mb and rs408511664 at 14.228 Mb) associated with coat colour in the MC1R gene on chromosome 14 with -log10(P) = 2.47E-14 and 1.00E-13, respectively. The consequence of rs409651063 was a missense variant (g.14231948 G>A) that caused an amino acid change (Asp105Asn); however, the second SNP (rs408511664) was a synonymous substitution and is an upstream variant (g.14228343G>A). Moreover, our PCR analysis revealed that the genotype of white sheep was exclusively homozygous (GG), whereas the genotypes of black-head sheep were mainly heterozygous (GA). Interestingly, allele-specific expression analysis (using the missense variant for the skin cDNA samples from black-head sheep) revealed that only the G allele was expressed in the skin covered with white hair, while both the G and A alleles were expressed in the skin covered with black hair. This finding indicated that the missense mutation that we identified is probably responsible for white coat colour in Tan sheep. Furthermore, qPCR analysis of MC1R mRNA level in the skin samples was significantly higher in black-head than white sheep and very significantly higher in GA than GG individuals. Taken together, these results help to elucidate the genetic mechanism underlying coat colour variation in Chinese indigenous sheep.


Assuntos
Cor de Cabelo/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Melanocortina/genética , Ovinos/genética , Animais , Receptor Tipo 1 de Melanocortina/metabolismo , Lã/metabolismo
3.
Sci Rep ; 10(1): 7303, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350296

RESUMO

Skin cancer risk information based on melanocortin-1 receptor (MC1R) variants could inform prevention and screening recommendations for Hispanics, but limited evidence exists on the impact of MC1R variants in Hispanic populations. We studied Hispanic subjects, predominately of Puerto Rican heritage, from Tampa, Florida, US, and Ponce, PR. Blood or saliva samples were collected by prospective recruitment or retrieved from biobanks for genotyping of MC1R variants and ancestry informative markers. Participant demographic and self-reported phenotypic information was collected via biobank records or questionnaires. We determined associations of MC1R genetic risk categories and phenotypic variables and genetic ancestry. Over half of participants carried MC1R variants known to increase risk of skin cancer, and there was diversity in the observed variants across sample populations. Associations between MC1R genetic risk groups and some pigmentation characteristics were identified. Among Puerto Ricans, the proportion of participants carrying MC1R variants imparting elevated skin cancer risk was consistent across quartiles of European, African, and Native American genetic ancestry. These findings demonstrate that MC1R variants are important for pigmentation characteristics in Hispanics and that carriage of high risk MC1R alleles occurs even among Hispanics with stronger African or Native American genetic ancestry.


Assuntos
Alelos , Hispano-Americanos/genética , Polimorfismo Genético , Receptor Tipo 1 de Melanocortina/genética , Neoplasias Cutâneas/genética , Pigmentação da Pele/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Porto Rico
4.
Anim Sci J ; 91(1): e13367, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32285552

RESUMO

Coat color is one of the important factors characterizing breeds for domestic animals. Melanocortin 1 receptor (MC1R) is a representative responsible gene for this phenotype. Two single-nucleotide polymorphisms (SNPs) in bovine MC1R gene, c.296T > C and c.310G>-, have been well characterized, but these SNPs are not enough to explain cattle coat color. As far as we know, MC1R genotypes of Kumamoto sub-breed of Japanese Brown cattle have not been analyzed. In the current study, genotyping for c.296T > C and c.310G>- was performed to elucidate the role of MC1R in determining the coat color of this sub-breed. As a result, most animals were e/e genotype, suggesting the coat color of this sub-breed is derived from the e allele of MC1R gene. However, we found six animals with E/e genotype, which coat color would be black theoretically. Subsequently, sequence comparison was performed with these animals to identify other polymorphisms affecting coat color, elucidating that these animals possessed the A allele of c.871G > A commonly. c.871G > A was a non-synonymous mutation in the seventh transmembrane domain, suggesting alteration of the function and/or the structure of MC1R protein. Our data indicated that the A allele of c.871G > A might be a loss-of-function mutation.


Assuntos
Bovinos/genética , Cor de Cabelo/genética , Fenótipo , Receptor Tipo 1 de Melanocortina/genética , Alelos , Animais , Feminino , Genótipo , Mutação com Perda de Função , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Melanocortina/química
5.
Clin Sci (Lond) ; 134(7): 695-710, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32167144

RESUMO

The clinical effectiveness of adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of melanocortins. However, which melanocortin receptors (MCR) convey this beneficial effect and if systemic or podocyte-specific mechanisms are involved remain uncertain. In vivo, wild-type (WT) mice developed heavy proteinuria and kidney dysfunction following Adriamycin insult, concomitant with focal segmental glomerulosclerosis (FSGS) and podocytopathy, marked by loss of podocin and synaptopodin, podocytopenia and extensive foot process effacement on electron microscopy. All these pathologic findings were prominently attenuated by NDP-MSH, a potent non-steroidogenic pan-MCR agonist. Surprisingly, MC1R deficiency in MC1R-null mice barely affected the severity of Adriamycin-elicited injury. Moreover, the beneficial effect of NDP-MSH was completely preserved in MC1R-null mice, suggesting that MC1R is likely non-essential for the protective action. A direct podocyte effect seems to contribute to the beneficial effect of NDP-MSH, because Adriamycin-inflicted cytopathic signs in primary podocytes prepared from WT mice were all mitigated by NDP-MSH, including apoptosis, loss of podocyte markers, de novo expression of the podocyte injury marker desmin, actin cytoskeleton derangement and podocyte hypermotility. Consistent with in vivo findings, the podoprotective activity of NDP-MSH was fully preserved in MC1R-null podocytes. Mechanistically, MC1R expression was predominantly distributed to glomerular endothelial cells in glomeruli but negligibly noted in podocytes in vivo and in vitro, suggesting that MC1R signaling is unlikely involved in direct podocyte protection. Ergo, melanocortin therapy protects against podocyte injury and ameliorates proteinuria and glomerulopathy in experimental FSGS, at least in part, via a podocyte-specific non-MC1R-mediated melanocortinergic signaling.


Assuntos
Albuminúria/prevenção & controle , Apoptose/efeitos dos fármacos , Glomerulosclerose Segmentar e Focal/prevenção & controle , Podócitos/efeitos dos fármacos , Receptor Tipo 1 de Melanocortina/agonistas , alfa-MSH/análogos & derivados , Albuminúria/induzido quimicamente , Albuminúria/metabolismo , Albuminúria/patologia , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Doxorrubicina , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade , Podócitos/metabolismo , Podócitos/ultraestrutura , Receptor Tipo 1 de Melanocortina/genética , Receptor Tipo 1 de Melanocortina/metabolismo , Transdução de Sinais , alfa-MSH/farmacologia
6.
Nat Commun ; 11(1): 745, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029712

RESUMO

Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC1, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC1 leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC1 is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Receptor Tipo 1 de Melanocortina/agonistas , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Variação Genética , Humanos , Imidazóis/farmacologia , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor Tipo 1 de Melanocortina/deficiência , Receptor Tipo 1 de Melanocortina/genética , Receptores Notch/antagonistas & inibidores , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , alfa-MSH/farmacologia
8.
Anim Genet ; 51(2): 235-248, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31977074

RESUMO

Melanocortin 1-receptor (MC1R) is one of the major genes that controls chicken plumage colour. In this study, we investigated the sequence and haplotype distribution of the MC1R gene in native Japanese chickens, along with non-Japanese chicken breeds. In total, 732 and 155 chickens from 30 Japanese and eight non-Japanese breeds respectively were used. Three synonymous and 11 non-synonymous nucleotide substitutions were detected, resulting in 15 haplotypes (H0-H14). Of these, three were newly found haplotypes (H9, H13 and H14), of which one (H9) was composed of known substitutions C69T, T212C, G274A and G636A. The second one (H13) possessed newly found non-synonymous substitution C919G, apart from the known substitutions C69T, G178A, G274A, G636A and T637C. The third one (H14) comprised a newly discovered substitution C919G in addition to the known C69T, G274A and G409A substitutions. The homozygote for this new haplotype exhibited wt like plumage despite the presence of G274A. In addition to discovering a new nucleotide substitution (C919G) and three new haplotypes, we defined the plumage colour of the bird that was homozygous for the A644C substitution (H5 haplotype) as wheaten-like for the first time; although the substitution has been already reported, its effect was not revealed. Besides detecting the new plumage colour, we also confirmed that the A427G and G274A substitutions contribute in expressing brownish and black plumage colour respectively, as reported by the previous studies. Moreover, we confirmed that the buttercup allele does not express black plumage despite possessing a G274A substitution, under the suppression effect of A644C. In contrast, the birds homozygous for the birchen allele presented solid black plumage, which was contradictory to the previous reports. In conclusion, we revealed a large diversity in the MC1R gene of native Japanese chicken breeds, along with the discovery of a new non-synonymous nucleotide substitution (C919G) and three novel haplotypes (H9, H13 and H14).


Assuntos
Proteínas Aviárias/genética , Galinhas/fisiologia , Plumas/fisiologia , Pigmentação/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Melanocortina/genética , Substituição de Aminoácidos , Animais , Proteínas Aviárias/metabolismo , Galinhas/genética , Cor , Feminino , Haplótipos , Masculino , Pigmentos Biológicos/genética , Pigmentos Biológicos/metabolismo , Receptor Tipo 1 de Melanocortina/metabolismo
9.
Int J Mol Sci ; 21(2)2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31968661

RESUMO

Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MTII using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MTII potently inhibited the migration, invasion, and colony-forming capability of melanoma cells. Moreover, topical MTII application significantly attenuated the tumor progression in mice bearing established melanoma. Histological analysis revealed that MTII therapy induced apoptosis while inhibiting the proliferation and neovaluarization in melanoma tissues. By immunoblot and immunohistochemical analysis, it was found that MTII dose-dependently increased the phosphatase and tensin homolog (PTEN) protein level while reducing PTEN phosphorylation, which resulted in the inhibition of AKT/nuclear factor kappa B (NFκB) signaling. Consistently, MTII treatment inhibited cyclooxygenase II (COX-2) expression and prostaglandin E2 (PGE2) production in melanoma cells. Finally, studies of antibody neutralization suggest that the melanocortin 1 receptor (MC1R) plays a critical role in MTII-induced PTEN upregulation and melanoma suppression. Together, these results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling. Hence, topical MTII therapy may facilitate a novel therapeutic strategy against melanoma.


Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Ciclo-Oxigenase 2/metabolismo , Melanoma Experimental/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Peptídeos Cíclicos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , alfa-MSH/análogos & derivados , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Dinoprostona/metabolismo , Humanos , Imuno-Histoquímica , Melanoma Experimental/metabolismo , Camundongos , Modelos Biológicos , PTEN Fosfo-Hidrolase/genética , Fosforilação , Receptor Tipo 1 de Melanocortina/genética , Receptor Tipo 1 de Melanocortina/metabolismo , Regulação para Cima/efeitos dos fármacos , alfa-MSH/administração & dosagem
10.
Pigment Cell Melanoma Res ; 33(1): 30-40, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398282

RESUMO

Homozygous loss of function of the melanocortin 1 receptor (MC1R) is associated with a pheomelanotic pigment phenotype and increased melanoma risk. MC1R heterozygosity is less well studied, although individuals inheriting one loss-of-function MC1R allele are also melanoma-prone. Using the K14-Scf C57BL/6J animal model whose skin is characterized by lifelong retention of interfollicular epidermal melanocytes like that of the human, we studied pigmentary, UV responses, and DNA repair capacity in the skin of variant Mc1r background. Topical application of forskolin, a skin-permeable pharmacologic activator of cAMP induction to mimic native Mc1r signaling, increased epidermal eumelanin levels, increased the capacity of Mc1r-heterozygous skin to resist UV-mediated inflammation, and enhanced the skin's ability to clear UV photolesions from DNA. Interestingly, topical cAMP induction also promoted melanin accumulation, UV resistance, and accelerated clearance in Mc1r fully intact skin. Together, our findings suggest that heterozygous Mc1r loss is associated with an intermediately melanized and DNA repair-proficient epidermal phenotype and that topical cAMP induction enhances UV resistance in Mc1r-heterozygous or Mc1r-wild-type individuals by increasing eumelanin deposition and by improving nucleotide excision repair.


Assuntos
AMP Cíclico/farmacologia , Melaninas/metabolismo , Receptor Tipo 1 de Melanocortina/genética , Pele/lesões , Pele/efeitos da radiação , Raios Ultravioleta , Animais , Colforsina/farmacologia , Reparo do DNA/efeitos da radiação , Heterozigoto , Inflamação/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monofenol Mono-Oxigenase/metabolismo , Fenótipo , Pele/efeitos dos fármacos
12.
Gen Comp Endocrinol ; 285: 113291, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31568758

RESUMO

Melanocortin-1 receptor (MC1R) has important roles in regulating pigmentation and inflammation. Melanocortin receptor accessory protein 2 (MRAP2) modulates trafficking, ligand binding, and signaling of mammalian melanocortin receptors. However, the effect of MRAP2 on fish MC1R has not been extensively studied. Herein, we cloned the orange-spotted grouper (Epinephelus coioides) mc1r, which had a 972 bp open reading frame encoding a putative protein of 323 amino acids. Grouper mc1r was mainly expressed in the brain, skin, testis, spleen, head kidney, and kidney. EcoMC1R showed high constitutive activities in both Gs-cAMP and ERK1/2 pathways, which could be differentially modulated by grouper MRAP2 (EcoMRAP2). Three agonists, including α-melanocyte-stimulating hormone (MSH), ß-MSH, and ACTH, could bind to EcoMC1R and dose-dependently increase intracellular cAMP production. EcoMRAP2 had no effect on the IC50 in binding assay or EC50 in cAMP assay; however, it dose-dependently decreased the cell surface expression and maximal response to the three agonists. EcoMRAP2 increased basal ERK1/2 activation but did not alter α-MSH-stimulated ERK1/2 activation. This study extends the knowledge base of fish MC1R pharmacology and its regulation by MRAP2.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Bass/metabolismo , Proteínas de Peixes/metabolismo , Receptor Tipo 1 de Melanocortina/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Bass/genética , AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Ligantes , Sistema de Sinalização das MAP Quinases , Filogenia , Receptor Tipo 1 de Melanocortina/química , Receptor Tipo 1 de Melanocortina/genética , Transdução de Sinais/efeitos dos fármacos
13.
Anim Genet ; 50(6): 712-717, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31475378

RESUMO

By studying genes associated with coat colour, we can understand the role of these genes in pigmentation but also gain insight into selection history. North European short-tailed sheep, including Swedish breeds, have variation in their coat colour, making them good models to expand current knowledge of mutations associated with coat colour in sheep. We studied ASIP and MC1R, two genes with known roles in pigmentation, and their association with black coat colour. We did this by sequencing the coding regions of ASIP in 149 animals and MC1R in 129 animals from seven native Swedish sheep breeds in individuals with black, white or grey fleece. Previously known mutations in ASIP [recessive black allele: g.100_105del (D5 ) and/or g.5172T>A] were associated with black coat colour in Klövsjö and Roslag sheep breeds and mutations in both ASIP and MC1R (dominant black allele: c.218T>A and/or c.361G>A) were associated with black coat colour in Swedish Finewool. In Gotland, Gute, Värmland and Helsinge sheep breeds, coat colour inheritance was more complex: only 11 of 16 individuals with black fleece had genotypes that could explain their black colour. These breeds have grey individuals in their populations, and grey is believed to be a result of mutations and allelic copy number variation within the ASIP duplication, which could be a possible explanation for the lack of a clear inheritance pattern in these breeds. Finally, we found a novel missense mutation in MC1R (c.452G>A) in Gotland, Gute and Värmland sheep and evidence of a duplication of MC1R in Gotland sheep.


Assuntos
Proteína Agouti Sinalizadora/genética , Mutação , Receptor Tipo 1 de Melanocortina/genética , Carneiro Doméstico/genética , Animais , Pigmentação , Carneiro Doméstico/classificação , Carneiro Doméstico/fisiologia
14.
Biochem Biophys Res Commun ; 518(4): 739-745, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31472961

RESUMO

We previously reported that the melanocortin-1 receptor (MC1R), a key regulator of melanogenesis, regulates cell migration; however, the detailed mechanism remained unknown. Since the homo-dimerization of MC1R by four inter-subunit disulfide bonds is known to be functionally important for melanogenesis, we investigated the importance of MC1R dimerization for cell migration. Unlike the wild-type MC1R, the dimerization-defective mutant MC1R in which four critical Cys residues were replaced with Ala residues (Cys35-267-273-275Ala) significantly inhibited melanin synthesis but enhanced cell migration in human MNT-1 and A375 melanoma cells. This suggests that there may be a reverse correlation between melanin synthesis and cell migration. Interestingly, melanoma cells expressing the dimerization-defective mutant exhibited enhanced expression of the cell surface heparan sulfate proteoglycan, syndecan-2, and knockdown of syndecan-2 expression decreased the mutant-mediated cell migration. Consistently, ASIP, an antagonist of MC1R, enhanced syndecan-2 expression and cell migration and reversed the α-melanocyte-stimulating hormone (α-MSH)-mediated inhibition of syndecan-2 expression. Furthermore, α-MSH reduced the cell migration of MNT1 cells expressing wild-type MC1R but not its dimerization-defective mutant. Together, these data strongly suggest that MC1R reversely regulates melanin synthesis and migration via the conformational changes induced by dimerization.


Assuntos
Movimento Celular/fisiologia , Melaninas/biossíntese , Melanoma/metabolismo , Receptor Tipo 1 de Melanocortina/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Melanoma/genética , Melanoma/patologia , Mutação , Conformação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Receptor Tipo 1 de Melanocortina/química , Receptor Tipo 1 de Melanocortina/genética , Sindecana-2/genética , Sindecana-2/metabolismo , alfa-MSH/farmacologia
15.
Cancer Epidemiol Biomarkers Prev ; 28(11): 1853-1856, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31488411

RESUMO

BACKGROUND: The Melanocortin 1 Receptor (MC1R) contributes to pigmentation, an important risk factor for developing melanoma. Evaluating SNPs in MC1R and association with race/ethnicity, skin type, and perceived cancer risk in a New Mexico (NM) population will elucidate the role of MC1R in a multicultural population. METHODS: We genotyped MC1R in 191 NMs attending a primary care clinic in Albuquerque. We obtained individuals' self-identified race/ethnicity, skin type, and perceived cancer risk. We defined genetic risk as carriage of any one or more of the nine most common SNPs in MC1R. RESULTS: We found that one MC1R SNP, R163Q (rs885479), was identified in 47.6% of self-identified Hispanics and 12.9% of non-Hispanic whites (NHW), making Hispanics at higher "genetic risk" (as defined by carrying one of the MC1R common variants). When we deleted R163Q from analyses, Hispanics were no longer at higher genetic risk (33.3%) compared with NHW (48.3%), consistent with melanoma rates, tanning ability, and lower perceived risk. Hispanics had a perceived risk significantly lower than NHW and a nonsignificant better tanning ability than NHW. CONCLUSIONS: The R163Q variant in MC1R may not be a risk factor for melanoma among NM Hispanics. This suggestion points to the need to carefully interpret genetic risk factors among specific populations. IMPACT: Genetic risk cannot be extrapolated from Northern European populations directly to non-European populations.


Assuntos
Receptor Tipo 1 de Melanocortina/genética , Variação Genética , Genótipo , Humanos , New Mexico
16.
Exp Dermatol ; 28(11): 1321-1327, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31520496

RESUMO

BACKGROUND: The melanocortin 1 receptor (MC1R) gene is one of the major determinants of skin pigmentation. It is a highly polymorphic gene and some of its polymorphisms have been related to specific skin phenotypes, increased risk of skin cancers and skin photoageing. Currently, its contribution to changes in dermal features in photo-exposed skin is unknown. OBJECTIVE: The main objective of this study is to evaluate the potential correlation between MC1R status and specific healthy photo-exposed skin characteristics. MATERIALS AND METHODS: Skin facial features were estimated by evaluation with standard digital photography with automated features count, reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) in 100 healthy women. Skin of the forearms was used as a control. RESULTS: The study found an association between RHC MC1R polymorphisms and dermal features in photo-exposed areas being represented by increased vessel density and pixel density in OCT (P = .025 and P = .001, respectively) and increased coarse collagen in RCM (P = .034), as compared to non-RHC subjects. To our knowledge this is previously unreported. Additionally, previously reported correlations between light hair colour and pigmented spots with MC1R RHC polymorphisms have been confirmed. CONCLUSIONS: Our results suggest the role of RHC MC1R variants in dermal variations of facial skin, as compared to non-RHC variants. To our knowledge this is previously unreported.


Assuntos
Receptor Tipo 1 de Melanocortina/genética , Envelhecimento da Pele/genética , Adulto , Feminino , Humanos , Microscopia Confocal , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia de Coerência Óptica
17.
Public Health Genomics ; 22(1-2): 58-68, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437847

RESUMO

BACKGROUND: Translational research in genomics has limited reach and requires efforts to broaden access and utility in diverse populations. Skin cancer is common and rates are rising, including among Hispanics. Germline variants in the melanocortin-1 receptor (MC1R) gene are common in the population and confer moderate risk for melanoma and basal cell cancers across skin types. Feedback about MC1R risk status may promote skin cancer risk awareness and risk reduction. AIMS: We examined the level of interest in pursuing MC1R testing, and patterns of interest across skin cancer perceived threat and control attitudes, cultural beliefs (family influence on health, health system distrust, cancer fatalism, skin cancer misconceptions), and health literacy. METHODS: We used a study website to inform primary care patients in Albuquerque, NM about the benefits and drawbacks of MC1R testing. Website logon, request of a saliva test kit, and return of the test kit (yes vs. no) were primary assessments of study interest and uptake. RESULTS: Of 499 participants provided with a test offer, 33% requested and returned the test. Lower family influence on participants' health was an important factor both overall and within ethnicity subgroups, and may indicate that primary care patients interested in skin cancer genetic testing see themselves as proactive health seekers, independent from family encouragement. Lower self-efficacy for skin cancer prevention was also an important characteristic of those who tested. CONCLUSION: As evidence for common genetic markers for skin cancer accumulates, these findings suggest characteristics of those most likely to pursue genetic testing for skin cancer risk.


Assuntos
Atitude Frente a Saúde , Diversidade Cultural , Letramento em Saúde , Hispano-Americanos/psicologia , Melanoma , Psicologia , Receptor Tipo 1 de Melanocortina , Neoplasias Cutâneas , Adulto , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Melanoma/etnologia , Melanoma/genética , Melanoma/psicologia , Pessoa de Meia-Idade , New Mexico/epidemiologia , Atenção Primária à Saúde/métodos , Receptor Tipo 1 de Melanocortina/análise , Receptor Tipo 1 de Melanocortina/genética , Neoplasias Cutâneas/etnologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/psicologia
18.
Forensic Sci Int Genet ; 42: 252-259, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31400656

RESUMO

Freckles or ephelides are hyperpigmented spots observed on skin surface mainly in European and Asian populations. Easy recognition and external visibility make prediction of ephelides, the potentially useful target in the field of forensic DNA phenotyping. Prediction of freckles would be a step forward in sketching the physical appearance of unknown perpetrators or decomposed cadavers for the forensic DNA intelligence purposes. Freckles are especially common in people with pale skin and red hair and therefore it is expected that predisposition to freckles may partially share the genetic background with other pigmentation traits. The first proposed freckle prediction model was developed based on investigation that involved variation of MC1R and 8 SNPs from 7 genes in a Spanish cohort [19]. In this study we examined 113 DNA variants from 46 genes previously associated with human pigmentation traits and assessed their impact on freckles presence in a group of 960 individuals from Poland. Nineteen DNA variants revealed associations with the freckle phenotype and the study also revealed that females have ∼1.8 higher odds of freckles presence comparing to males (p-value = 9.5 × 10-5). Two alternative prediction models were developed using regression methods. A simplified binomial 12-variable model predicts the presence of ephelides with cross-validated AUC = 0.752. A multinomial 14-variable model predicts one of three categories - non-freckled, medium freckled and heavily freckled. The two extreme categories, non-freckled and heavily freckled were predicted with moderately high accuracy of cross-validated AUC = 0.754 and 0.792, respectively. Prediction accuracy of the intermediate category was lower, AUC = 0.657. The study presents novel DNA models for prediction of freckles that can be used in forensic investigations and emphasizes significance of pigmentation genes and sex in predictive DNA analysis of freckles.


Assuntos
Melanose/genética , Modelos Genéticos , Miosinas Cardíacas/genética , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteínas da Matriz Extracelular/genética , Feminino , Glicoproteínas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fatores Reguladores de Interferon/genética , Modelos Logísticos , Masculino , Proteínas de Membrana Transportadoras/genética , Monofenol Mono-Oxigenase/genética , Cadeias Pesadas de Miosina/genética , Proteínas Nucleares/genética , Coativadores de Receptor Nuclear/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Melanocortina/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA , Fatores Sexuais , Pigmentação da Pele , Ubiquitina-Proteína Ligases
19.
Mol Pharm ; 16(9): 3904-3915, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31318566

RESUMO

Melanocortin 1 receptor (MC1R) is under investigation as a target for drug delivery for metastatic melanoma therapy and imaging. The purpose of this study was to determine the potential of using BRAF inhibitors (BRAFi) and histone deacetylase inhibitors (HDACi) to enhance the delivery of MC1R-targeted radiolabeled peptide ([212Pb]DOTA-MC1L) by pharmacologically upregulating the MC1R expression in metastatic melanoma cells and tumors. MC1R expression was analyzed in de-identified melanoma biopsies by immunohistochemical staining. Upregulation of MC1R expression was determined in BRAFV600E cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, flow cytometry, and receptor-ligand binding assays. The role of microphthalmia-associated transcription factor (MITF) in the upregulation of MC1R was also examined in A2058 and MEWO cells. The effectiveness of [212Pb]DOTA-MC1L α-particle radiotherapy in combination with BRAFi and/or HDACi was determined in athymic nu/nu mice bearing A2058 and MEWO human melanoma xenografts. High expression of MC1R was observed in situ in clinical melanoma biopsies. BRAFi and HDACi significantly increased the MC1R expression (up to 10-fold in mRNA and 4-fold in protein levels) via MITF-dependent pathways, and this increase led to enhanced ligand binding on the cell surface. Inhibition of MITF expression antagonized the upregulation of MC1R in both BRAFV600E and BRAFWT cells. Combining [212Pb]DOTA-MC1L with BRAFi and/or HDACi improved the tumor response by increasing the delivery of 212Pb α-particle emissions to melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDACi and BRAFi could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Melanoma/tratamento farmacológico , Melanoma/radioterapia , Receptor Tipo 1 de Melanocortina/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/radioterapia , Regulação para Cima/efeitos dos fármacos , Partículas alfa/uso terapêutico , Animais , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Imidazóis/farmacologia , Radioisótopos de Chumbo/química , Melanoma/patologia , Camundongos Nus , Fator de Transcrição Associado à Microftalmia , Oximas/farmacologia , Fenilbutiratos/farmacologia , Projetos Piloto , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Melanocortina/genética , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Neoplasias Cutâneas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA