MGRN1 as a Phenotypic Determinant of Human Melanoma Cells and a Potential Biomarker

Mahogunin Ring Finger 1 (MGRN1), a ubiquitin ligase expressed in melanocytes, interacts with the α melanocyte-stimulating hormone receptor, a well-known melanoma susceptibility gene. Previous studies showed that MGRN1 modulates the phenotype of mouse melanocytes and melanoma cells, with effects on pigmentation, shape, and motility. Moreover, MGRN1 knockdown augmented the burden of DNA breaks in mouse cells, indicating that loss of MGRN1 promoted genomic instability. However, data concerning the roles of MGRN1 in human melanoma cells remain scarce. We analyzed MGRN1 knockdown in human melanoma cells. Transient MGRN1 depletion with siRNA or permanent knockdown in human melanoma cells by CRISPR/Cas9 caused an apparently MITF-independent switch to a more dendritic phenotype. Lack of MGRN1 also increased the fraction of human cells in the S phase of the cell cycle and the burden of DNA breaks but did not significantly impair proliferation. Moreover, in silico analysis of publicly available melanoma datasets and estimation of MGRN1 in a cohort of clinical specimens provided preliminary evidence that MGRN1 expression is higher in human melanomas than in normal skin or nevi and pointed to an inverse correlation of MGRN1 expression in human melanoma with patient survival, thus suggesting potential use of MGRN1 as a melanoma biomarker.This research was funded by grant SAF2018_RTI2018-094929-B-I00 financed by FEDER/Ministerio de Ciencia e Innovación—Agencia Estatal de Investigación (Spain) (to C.J.-C. and J.C.G.-B.), and by grant UPV/EHU GIU20/035 (to S.A and M.D.B.)

Controlled trial of balance training using a video game console in community-dwelling older adults

gamification is a potentially attractive option for improving balance and reducing falls. to assess the effect of balance training using the NintendoTM Wii game console on balance (primary outcome), falls and fear of falling. quasi-randomised, open-label, controlled clinical trial in parallel groups, carried out on community-dwelling patients over 70 years, able to walk independently. Participants were assigned 1:1 to the intervention or control group. Balance training was conducted using the Nintendo WiiFit TM twice a week for 3 months. Balance was assessed using the Tinetti balance test (primary outcome), the unipedal stance and the Wii balance tests at baseline, 3 months and 1 year. Falls were recorded and Fear of falling was assessed by the Falls Efficacy Scale (Short-FES-I). 1,016 subjects were recruited (508 in both the intervention and the control group; of whom 274 and 356 respectively completed the 3-month assessment). There was no between-group difference in the Tinetti balance test score, with a baseline mean of 14.7 (SD 1.8) in both groups, and 15.2 (1.3) at 3 months in the intervention group compared to 15.3 (1.7) in controls; the between-group difference was 0.06 (95% CI 0.30-0.41). No differences were seen in any of the other balance tests, or in incident falls. There was a reduction in the fear of falling at 3 months, but no effect at 1 year. the study found no effect of balance training using the Nintendo TM Wii on balance or falls in older community-dwelling patients. The study protocol is available at clinicaltrials.gov under the code NCT02570178

Isoenzimas de tirosinasa en melanocitos malignos : función de la proteina relacionada con tirosinasa 1 / Celia Jimenez-Cervantes Frigols ; directores José Carlos García-Borrón Martínez, Francisco Solano Muñoz.

Tesis-Universidad de Murcia.Consulte la tesis en: BCA. GENERAL. ARCHIVO UNIVERSITARIO. T.M.-1061.CRAI CIENCIAS. DEPOSITO. T.D. 169

Melanocortin 1 receptor mutations impact differentially on signalling to the cAMP and the ERK mitogen-activated protein kinase pathways

AbstractMelanocortin 1 receptor (MC1R), a Gs protein-coupled receptor expressed in melanocytes, is a major determinant of skin pigmentation, phototype and cancer risk. MC1R activates cAMP and mitogen-activated protein kinase ERK1/ERK2 signalling. When expressed in rat pheochromocytoma cell line cells, the R151C, R160W and D294H MC1R variants associated with melanoma and impaired cAMP signalling mediated ERK activation and ERK-dependent, agonist-induced neurite outgrowth comparable with wild-type. Dose–response curves for ERK activation and cAMP production indicated higher sensitivity of the ERK response. Thus, the melanoma-associated MC1R mutations impact differently on cAMP and ERK signalling, suggesting that cAMP is not responsible for functional coupling of MC1R to the ERK cascade

Functional interplay between secreted ligands and receptors in melanoma

Melanoma, the most aggressive form of skin cancer, results from the malignant transformation of melanocytes located in the basement membrane separating the epidermal and dermal skin compartments. Cutaneous melanoma is often initiated by solar ultraviolet radiation (UVR)-induced mutations. Melanocytes intimately interact with keratinocytes, which provide growth factors and melanocortin peptides acting as paracrine regulators of proliferation and differentiation. Keratinocyte-derived melanocortins activate melanocortin-1 receptor (MC1R) to protect melanocytes from the carcinogenic effect of UVR. Accordingly, MC1R is a major determinant of susceptibility to melanoma. Despite extensive phenotypic heterogeneity and high mutation loads, the molecular basis of melanomagenesis and the molecules mediating the crosstalk between melanoma and stromal cells are relatively well understood. Mutations of intracellular effectors of receptor tyrosine kinase (RTK) signalling, notably NRAS and BRAF, are major driver events more frequent than mutations in RTKs. Nevertheless, melanomas often display aberrant signalling from RTKs such as KIT, ERRB1-4, FGFR, MET and PDGFR, which contribute to disease progression and resistance to targeted therapies. Progress has also been made to unravel the role of the tumour secretome in preparing the metastatic niche. However, key aspects of the melanoma-stroma interplay, such as the molecular determinants of dormancy, remain poorly understood.Work by the authors is supported by grants SAF2015-67092-R (to CJ-C and JCG-B) and SAF2016-75702-R (to BS-L) from the Mineco (Spain) and FEDER (European Community) and 19875/GERM/15 from the Fundación Seneca, Comunidad Autónoma Región de Murcia (CARM) (to CJ-C and JCG-B). C Herraiz holds a Juan de la Cierva-Incorporación fellowship from Mineco (Spain).Peer reviewe