The protective role of MC1R in chromosome stability and centromeric integrity in melanocytes

AbstractVariants in the melanocortin-1 receptor (MC1R) gene, encoding a trimeric G-protein-coupled receptor and activated by α-melanocyte-stimulating hormone (α-MSH), are frequently associated with red or blonde hair, fair skin, freckling, and skin sensitivity to ultraviolet (UV) light. Several red hair color variants of MC1R are also associated with increased melanoma risk. MC1R variants affect melanoma risk independent of phenotype. Here, we demonstrated that MC1R is a critical factor in chromosome stability and centromere integrity in melanocytes. α-MSH/MC1R stimulation prevents melanocytes from UV radiation-induced damage of chromosome stability and centromere integrity. Mechanistic studies indicated that α-MSH/MC1R-controlled chromosome stability and centromeric integrity are mediated by microphthalmia-associated transcription factor (Mitf), a transcript factor needed for the α-MSH/MC1R signaling and a regulator in melanocyte development, viability, and pigment production. Mitf directly interacts with centromere proteins A in melanocytes. Given the connection among MC1R variants, red hair/fair skin phenotype, and melanoma development, these studies will help answer a question with clinical relevance “why red-haired individuals are so prone to developing melanoma”, and will lead to the identification of novel preventive and therapeutic strategies for melanomas, especially those with redheads.

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Melanoma risk prediction models

Vojnosanitetski pregled ◽

10.2298/vsp130722045n ◽

2014 ◽

Vol 71 (8) ◽

pp. 757-766

Author(s):

Jelena Nikolic ◽

Tatjana Loncar-Turukalo ◽

Srdjan Sladojevic ◽

Marija Marinkovic ◽

Zlata Janjic

Keyword(s):

Risk Factors ◽

At Risk ◽

High Risk ◽

Prediction Models ◽

Significant Risk ◽

Prognostic Models ◽

Hair Color ◽

Melanoma Risk ◽

Data Mining Algorithms ◽

Red Hair

Background/Aim. The lack of effective therapy for advanced stages of melanoma emphasizes the importance of preventive measures and screenings of population at risk. Identifying individuals at high risk should allow targeted screenings and follow-up involving those who would benefit most. The aim of this study was to identify most significant factors for melanoma prediction in our population and to create prognostic models for identification and differentiation of individuals at risk. Methods. This case-control study included 697 participants (341 patients and 356 controls) that underwent extensive interview and skin examination in order to check risk factors for melanoma. Pairwise univariate statistical comparison was used for the coarse selection of the most significant risk factors. These factors were fed into logistic regression (LR) and alternating decision trees (ADT) prognostic models that were assessed for their usefulness in identification of patients at risk to develop melanoma. Validation of the LR model was done by Hosmer and Lemeshow test, whereas the ADT was validated by 10-fold cross-validation. The achieved sensitivity, specificity, accuracy and AUC for both models were calculated. The melanoma risk score (MRS) based on the outcome of the LR model was presented. Results. The LR model showed that the following risk factors were associated with melanoma: sunbeds (OR = 4.018; 95% CI 1.724- 9.366 for those that sometimes used sunbeds), solar damage of the skin (OR = 8.274; 95% CI 2.661-25.730 for those with severe solar damage), hair color (OR = 3.222; 95% CI 1.984-5.231 for light brown/blond hair), the number of common naevi (over 100 naevi had OR = 3.57; 95% CI 1.427-8.931), the number of dysplastic naevi (from 1 to 10 dysplastic naevi OR was 2.672; 95% CI 1.572-4.540; for more than 10 naevi OR was 6.487; 95%; CI 1.993-21.119), Fitzpatricks phototype and the presence of congenital naevi. Red hair, phototype I and large congenital naevi were only present in melanoma patients and thus were strongly associated with melanoma. The percentage of correctly classified subjects in the LR model was 74.9%, sensitivity 71%, specificity 78.7% and AUC 0.805. For the ADT percentage of correctly classified instances was 71.9%, sensitivity 71.9%, specificity 79.4% and AUC 0.808. Conclusion. Application of different models for risk assessment and prediction of melanoma should provide efficient and standardized tool in the hands of clinicians. The presented models offer effective discrimination of individuals at high risk, transparent decision making and real-time implementation suitable for clinical practice. A continuous melanoma database growth would provide for further adjustments and enhancements in model accuracy as well as offering a possibility for successful application of more advanced data mining algorithms.

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Identification of a Novel Streptococcal Gene Cassette Mediating SOS Mutagenesis in Streptococcus uberis

Journal of Bacteriology ◽

10.1128/jb.00473-07 ◽

2007 ◽

Vol 189 (14) ◽

pp. 5210-5222 ◽

Cited By ~ 23

Author(s):

Emilia Varhimo ◽

Kirsi Savijoki ◽

Jari Jalava ◽

Oscar P. Kuipers ◽

Pekka Varmanen

Keyword(s):

Uv Light ◽

Streptococcus Thermophilus ◽

Gene Cassette ◽

Repeat Sequence ◽

Mobile Dna ◽

Mobility Shift ◽

Gene Encoding ◽

Sos Mutagenesis ◽

Streptococcus Uberis ◽

Y Family

ABSTRACT Streptococci have been considered to lack the classical SOS response, defined by increased mutation after UV exposure and regulation by LexA. Here we report the identification of a potential self-regulated SOS mutagenesis gene cassette in the Streptococcaceae family. Exposure to UV light was found to increase mutations to antibiotic resistance in Streptococcus uberis cultures. The mutational spectra revealed mainly G:C→A:T transitions, and Northern analyses demonstrated increased expression of a Y-family DNA polymerase resembling UmuC under DNA-damaging conditions. In the absence of the Y-family polymerase, S. uberis cells were sensitive to UV light and to mitomycin C. Furthermore, the UV-induced mutagenesis was almost completely abolished in cells deficient in the Y-family polymerase. The gene encoding the Y-family polymerase was localized in a four-gene operon including two hypothetical genes and a gene encoding a HdiR homolog. Electrophoretic mobility shift assays demonstrated that S. uberis HdiR binds specifically to an inverted repeat sequence in the promoter region of the four-gene operon. Database searches revealed conservation of the gene cassette in several Streptococcus species, including at least one genome each of Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mitis, Streptococcus sanguinis, and Streptococcus thermophilus strains. In addition, the umuC operon was localized in several mobile DNA elements of Streptococcus and Lactococcus species. We conclude that the hdiR-umuC-ORF3-ORF4 operon represents a novel gene cassette capable of mediating SOS mutagenesis among members of the Streptococcaceae.

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Glutathione Reductase and a Mitochondrial Thioredoxin Play Overlapping Roles in Maintaining Iron-Sulfur Enzymes in Fission Yeast

Eukaryotic Cell ◽

10.1128/ec.00244-06 ◽

2006 ◽

Vol 5 (11) ◽

pp. 1857-1865 ◽

Cited By ~ 39

Author(s):

Ji-Yoon Song ◽

Joonseok Cha ◽

Joon Lee ◽

Jung-Hye Roe

Keyword(s):

Fission Yeast ◽

Respiration Rate ◽

Normal Level ◽

Iron Homeostasis ◽

Critical Factor ◽

High Ratio ◽

Gene Encoding ◽

Iron Sulfur ◽

Mitochondrial Aconitase ◽

Multicopy Suppressors

ABSTRACT In the fission yeast Schizosaccharomyces pombe, the pgr1 + gene encoding glutathione (GSH) reductase (GR) is essentially required for cell survival. Depletion of GR caused proliferation arrest at the G1 phase of the cell cycle under aerobic conditions. Multicopy suppressors that restore growth were screened, and one effective suppressor was found to be the trx2 + gene, encoding a mitochondrial thioredoxin. This suggests that GR is critically required for some mitochondrial function(s). We found that GR resides in both cytosolic and organellar fractions of the cell. Depletion of GR lowered the respiration rate and the activity of oxidation-labile Fe-S enzymes such as mitochondrial aconitase and cytosolic sulfite reductase. Trx2 did not reverse the high ratio of oxidized glutathione to GSH or the low respiration rate observed in GR-depleted cells. However, it brought the activity of oxidation-labile Fe-S enzymes to a normal level, suggesting that the maintenance of Fe-S enzymes is a critical factor in the survival of S. pombe. The activity of succinate dehydrogenase, an oxidation-insensitive Fe-S enzyme, however, was not affected by GR depletion, suggesting that GR is not required for the biogenesis of the Fe-S cluster. The total iron content was greatly increased by GR depletion and was brought to a nearly normal level by Trx2. These results indicate that the essentiality of GR in the aerobic growth of S. pombe is derived from its role in maintaining oxidation-labile Fe-S enzymes and iron homeostasis.

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An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background

Nature ◽

10.1038/nature11624 ◽

2012 ◽

Vol 491 (7424) ◽

pp. 449-453 ◽

Cited By ~ 281

Author(s):

Devarati Mitra ◽

Xi Luo ◽

Ann Morgan ◽

Jin Wang ◽

Mai P. Hoang ◽

...

Keyword(s):

Ultraviolet Radiation ◽

Red Hair ◽

Fair Skin

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Analytical problems encountered in determining aluminum status from hair in controls and hemodialyzed patients.

Clinical Chemistry ◽

10.1093/clinchem/34.11.2253 ◽

1988 ◽

Vol 34 (11) ◽

pp. 2253-2255 ◽

Cited By ~ 6

Author(s):

P Chappuis ◽

L Duhaux ◽

F Paolaggi ◽

M C de Vernejoul ◽

F Rousselet

Keyword(s):

Critical Factor ◽

Hair Color ◽

Single Tube ◽

Control Subjects

Abstract The problems involved in evaluating aluminum concentrations in hair are reviewed, especially those concerning removal of contaminating metals, a critical factor. In the few published studies of Al concentrations in hair, acetone was usually used for its removal. Here, its use in the washing sequence was found to give less precise results and higher Al values than the use of isopropanol. With isopropanol, the whole analysis can be done in a single tube. We compared results with those in the literature. We found that the Al concentration in the hair of control subjects was not related to sex or hair color and that there was a highly significant (P less than 0.001) difference between values for control subjects and hemodialyzed patients: 126 (SD 58) nmol/g, n = 49, vs 226 (SD 104) nmol/g, n = 39, respectively.

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Calcium- and Calcineurin-Independent Roles for Calmodulin in Cryptococcus neoformans Morphogenesis and High-Temperature Growth

Eukaryotic Cell ◽

10.1128/ec.4.6.1079-1087.2005 ◽

2005 ◽

Vol 4 (6) ◽

pp. 1079-1087 ◽

Cited By ~ 56

Author(s):

Peter R. Kraus ◽

Connie B. Nichols ◽

Joseph Heitman

Keyword(s):

High Temperature ◽

Cryptococcus Neoformans ◽

Insertional Mutagenesis ◽

Pathogenic Fungus ◽

Critical Factor ◽

Growth Defect ◽

Insertion Mutant ◽

Gene Encoding ◽

Temperature Growth ◽

New Genes

ABSTRACT The function of calcium as a signaling molecule is conserved in eukaryotes from fungi to humans. Previous studies have identified the calcium-activated phosphatase calcineurin as a critical factor in governing growth of the human pathogenic fungus Cryptococcus neoformans at mammalian body temperature. Here, we employed insertional mutagenesis to identify new genes required for growth at 37°C. One insertion mutant, cam1-ts, that displayed a growth defect at 37°C and hypersensitivity to the calcineurin inhibitor FK506 at 25°C was isolated. Both phenotypes were linked to the dominant marker in genetic crosses, and molecular analysis revealed that the insertion occurred in the 3′ untranslated region of the gene encoding the calcineurin activator calmodulin (CAM1) and impairs growth at 37°C by significantly reducing calmodulin mRNA abundance. The CAM1 gene was demonstrated to be essential using genetic analysis of a CAM1/cam1Δ diploid strain. In the absence of calcineurin function, the cam1-ts mutant displayed a severe morphological defect with impaired bud formation. Expression of a calmodulin-independent calcineurin mutant did not suppress the growth defect of the cam1-ts mutant at 37°C, indicating that calmodulin promotes growth at high temperature via calcineurin-dependent and -independent pathways. In addition, a Ca2+-binding-defective allele of CAM1 complemented the 37°C growth defect, FK506 hypersensitivity, and morphogenesis defect of the cam1-ts mutant. Our findings reveal that calmodulin performs Ca2+- and calcineurin-independent and -dependent roles in controlling C. neoformans morphogenesis and high-temperature growth.

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Melanocytes expressing MC1R polymorphisms associated with red hair color have altered MSH-ligand activated pigmentary responses in coculture with keratinocytes

Journal of Cellular Physiology ◽

10.1002/jcp.21318 ◽

2008 ◽

Vol 215 (2) ◽

pp. 344-355 ◽

Cited By ~ 19

Author(s):

Donald W. Roberts ◽

Richard A. Newton ◽

J. Helen Leonard ◽

Richard A. Sturm

Keyword(s):

Hair Color ◽

Red Hair

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The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2

Journal of Experimental Medicine ◽

10.1084/jem.20150851 ◽

2016 ◽

Vol 213 (5) ◽

pp. 687-696 ◽

Cited By ~ 44

Author(s):

Erin C. Zook ◽

Kevin Ramirez ◽

Xiaohuan Guo ◽

Grant van der Voort ◽

Mikael Sigvardsson ◽

...

Keyword(s):

Transcription Factor ◽

Messenger Rna ◽

Critical Factor ◽

Protective Role ◽

Lymphoid Cells ◽

Allergic Lung Inflammation ◽

Factor Inhibitor ◽

Group 2

Group 2 innate lymphoid cells (ILC2s) are a subset of ILCs that play a protective role in the response to helminth infection, but they also contribute to allergic lung inflammation. Here, we report that the deletion of the ETS1 transcription factor in lymphoid cells resulted in a loss of ILC2s in the bone marrow and lymph nodes and that ETS1 promotes the fitness of the common progenitor of all ILCs. ETS1-deficient ILC2 progenitors failed to up-regulate messenger RNA for the E protein transcription factor inhibitor ID2, a critical factor for ILCs, and these cells were unable to expand in cytokine-driven in vitro cultures. In vivo, ETS1 was required for the IL-33–induced accumulation of lung ILC2s and for the production of the T helper type 2 cytokines IL-5 and IL-13. IL-25 also failed to elicit an expansion of inflammatory ILC2s when these cells lacked ETS1. Our data reveal ETS1 as a critical regulator of ILC2 expansion and cytokine production and implicate ETS1 in the regulation of Id2 at the inception of ILC2 development.

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A Large French Case-Control Study Emphasizes the Role of RareMc1RVariants in Melanoma Risk

BioMed Research International ◽

10.1155/2014/925716 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 11

Author(s):

Hui-Han Hu ◽

Mériem Benfodda ◽

Nicolas Dumaz ◽

Steven Gazal ◽

Vincent Descamps ◽

...

Keyword(s):

Rare Variants ◽

Skin Pigmentation ◽

Coding Region ◽

Melanoma Risk ◽

Red Hair ◽

French Case ◽

Melanoma Patients ◽

Definition Of ◽

Population Attributable Risks

Background. TheMC1Rgene implicated in melanogenesis and skin pigmentation is highly polymorphic. Several alleles are associated with red hair and fair skin phenotypes and contribute to melanoma risk.Objective. This work aims to assess the effect of different classes ofMC1Rvariants, notably rare variants, on melanoma risk.Methods.MC1Rcoding region was sequenced in 1131 melanoma patients and 869 healthy controls.MC1Rvariants were classified as RHC (R) and non-RHC (r). Rare variants (frequency < 1%) were subdivided into two subgroups, predicted to be damaging (D) or not (nD).Results. BothRandralleles were associated with melanoma (OR = 2.66 [2.20–3.23] and 1.51 [1.32–1.73]) and had similar population attributable risks (15.8% and 16.6%). We also identified 69 rare variants, of which 25 were novel.Dvariants were strongly associated with melanoma (OR = 2.38 [1.38–4.15]) and clustered in the sameMC1Rdomains asRalleles (intracellular 2, transmembrane 2 and 7).Conclusion. This work confirms the role ofRandralleles in melanoma risk in the French population and proposes a novel class of rareDvariants as important melanoma risk factors. These findings may improve the definition of high-risk subjects that could be targeted for melanoma prevention and screening.

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