Summary
We reported earlier on the oncogenic properties of Grm1 by demonstrating that stable Grm1‐mouse‐melanocytic clones proliferate in the absence of growth supplement and anchorage in vitro. In ...addition, these clones also exhibit aggressive tumorigenic phenotypes in vivo with short latency in tumor formation in both immunodeficient and syngeneic mice. We also detected strong activation of AKT in allograft tumors specifically AKT2 as the predominant isoform involved. In parallel, we assessed several human melanoma biopsy samples and found again that AKT2 was the predominantly activated AKT in these human melanoma biopsies. In cultured stable Grm1‐mouse‐melanocytic clones, as well as an metabotropic glutamate receptor 1 (Grm1) expressing human melanoma cell line, C8161, stimulation of Grm1 by its agonist led to the activation of AKT, while preincubation with Grm1‐antagonist abolished Grm1‐agonist‐induced AKT activation. In addition, a reduction in tumor volume of Grm1‐mouse‐melanocytic‐allografts was detected in the presence of small interfering AKT2 RNA (siAKT2). Taken together, these results showed that, in addition to the MAPK pathway previously reported being a downstream target of stimulated Grm1, AKT2 is another downstream target in Grm1 mediated melanocyte transformation.
Data obtained from a mouse model indicated that the ectopic expression of the Grm1 gene is sufficient for transforming melanocytes and causing malignant melanoma in vivo. In addition, it has also ...been documented that the GRM1 gene is aberrantly expressed in human melanomas. Here we have performed a genetic association study to elucidate whether the GRM1 gene contributes to human melanoma susceptibility. To carry out this study, we initially genotyped 250 melanoma patients and 329 nonselected and nonrelated controls with three single nucleotide polymorphisms, rs854145, rs362962 and rs6923492, located in the intron 1, intron 4 and exon 10 of the GRM1 gene, respectively. To perform sample genotyping, we used pyrosequencing techniques. Regarding rs854145 and rs6923492, there were no differences in genotypic distribution or allelic frequency between patients and controls. However, we observed (i) a higher frequency of patients carrying the C allele of rs362962 than in controls (OR=1.40, CI=1.01-1.95, P=0.045), and (ii) that difference became greater in a subgroup of patients with a low level of sun exposure and tumours located on the trunk and extremities (OR=2.10, CI=1.26-3.51, P=0.0039). To confirm these observations, the sample size of both patient and control groups was increased. In total, 464 patients and 561 controls were genotyped for the rs362962 polymorphism. Only the second observation was confirmed (OR=1.69, CI=1.16-2.47, P=0.0064). Our results suggest that the GRM1 gene may contribute to melanoma susceptibility in that specific group of patients.
The metabotropic glutamate (mGlu) 1 receptor, coded by the
GRM1
gene, is involved in synaptic activities, learning and neuroprotection. Eleven different mouse
Grm1
mutations, either induced or ...spontaneously occurring, have been reported, including one from our group. All the mutations result in a complex phenotype with ataxia and intention tremor in mice. Moreover, autoantibodies against mGlu1 receptor have been associated with paraneoplastic cerebellar ataxia in humans. In spite of the large clinical and genetic heterogeneity displayed by the inherited forms of cerebellar ataxia, forms remain with a yet unknown molecular definition. With the evidence coming out from mouse models and from paraneoplastic ataxia, it seems that
GRM1
represents a good candidate gene for early-onset ataxia forms, though no
GRM1
mutations have thus far been looked for. The aim of this study was to investigate the possible involvement of
GRM1
in early-onset or familial forms of ataxia. We searched for gene mutations in a panel of patients with early-onset ataxia as yet molecularly undefined. No causative mutations were found, though we detected synonymous variants in the exons and changes in flanking intronic sequences which are unlikely to alter correct splicing upon bioinformatics prediction. As for other known forms of inherited ataxias, absence of mutations in
GRM1
seems to suggest a relatively low frequency in cerebellar ataxias.
We describe a novel spontaneous autosomal recessive mutation, cervelet-4 (crv4), which arose in a BALB/c strain. Mice homozygous for the mutation exhibit principally a reduced body size, a congenital ...neurological phenotype characterized by ataxic gait and intention tremor, with no gross anomalies observed in brain or cerebellum, and skeletal anomalies. Using linkage analysis, we mapped the crv4 locus to the proximal region of chromosome 10, at the location of the Grm1 gene. Genetic complementation crosses between crv4 and Grm1 KO mice confirmed that crv4 is a new allele of Grm1. Molecular analysis of the Grm1 gene in mutant mice revealed the insertion of a 190-bp LTR fragment in intron 4. Our results also indicated that the presence of the LTR fragment caused the disruption of the Grm1 normal splicing process and complete absence of the wild-type protein. crv4 is an interesting model to extend the study of Grm1 function and the pathological effects of Grm1 deficiency in vivo.
Identifying new drugs and targets for melanoma therapy is critical, considering that melanoma, the most dangerous form of skin cancer, is resistant to currently available therapeutics. Much work has ...been focused on finding novel drugs and exploring different treatment options that could increase the overall survival of patients. In our laboratory we have developed mouse models to study melanoma. We discovered that aberrant expression of metabotropic glutamate receptor 1 (Grm1) in melanocytes promotes melanoma development in vivo. Grm1 is a seven transmembrane domain G-protein coupled receptor that is normally expressed and functional in the central nervous system. The natural ligand of Grm1 is glutamate. Signaling by the major neurotransmitter glutamate has been well characterized in neuronal cells; however glutamate signaling in other tissues is not well understood. We demonstrated that Grm1 signaling in melanoma cells is mediated by the Ras/Raf/MEK/ERK pathway, one of the major pathways previously shown to be activated in human melanoma cells. Based on these earlier studies and results from our recent work, we predict that inhibition of Grm1 signaling and its downstream cascade may potentially provide new, effective therapies for melanoma patients. In this review, we propose several attractive targets.
Glutamate toxicity plays a key role in neuronal cell death. The aim of this study was to investigate whether three single nucleotide polymorphisms (SNPs) (rs2073287, intron; rs2942, Lys931Lys; ...rs6923492, Ser993Pro) of glutamate receptor, metabotropic 1 (
GRM1
) were associated with the development and clinical features of stroke. We recruited 365 control subjects and 195 stroke patients consisted of 119 ischemic stroke (IS) and 76 intracerebral hemorrhage (ICH). All stroke patients were divided into clinical subgroups according to the scores of the National Institutes of Health Stroke Survey (NIHSS, < 6 and ≥ 6) and Modified Barthel Index (MBI, < 60 and ≥60). SNPStats and SPSS 18.0 were conducted to evaluate odds ratios (ORs), 95% confidence intervals (CIs), and
P
values. Multiple logistic regression models were performed to analyze the genetic data. A rs2073287 SNP of
GRM1
was associated with the susceptibility of stroke (IS+ ICH) (
P
=0.002, OR=1.49, 95% CI=1.16-1.92 in allele frequencies). The rs2073287 was also associated with the development of IS (
P
=0.028, OR=1.40, 95% CI= 1.04-1.89 in allele frequencies) and ICH (
P
=0.006, OR=1.65, 95% CI=1.16–2.35 in allele frequencies). The G allele frequencies of rs2073287 in stroke (IS+ ICH), IS, and ICH were higher than in the control group, respectively. The rs2942 and rs6923492 were not related to stroke (IS+ICH), IS, and ICH, respectively. These results suggested that the G allele of rs2073287 could be a risk factor to the susceptibility of stroke in Korean population.
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