Development of Early Melanocytic Lesions in Transgenic Mice Predisposed to Melanoma

Zhu, Hua; Reuhl, Kenneth R.; Botha, Rosanne; Ryan, Kevin; Wei, Joyce; Chen, Suzie

doi:10.1034/j.1600-0749.2000.130307.x

Cited by 21 publications

(20 citation statements)

References 23 publications

(45 reference statements)

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“…In TG3 mice at PND 15, clusters of melanocytes likely derived from clonal expansion were noted. By PND 30, large rounded and heavily pigmented melanocytes that resembled those observed in adult TG3 mice were noted on the skin, choroid plexus and harderian gland of the eye supporting the notion that the origin of these pigmented lesions were neural crest derived melanocytes [65]. From genome mapping studies on the TG3 mouse line, we determined that there was only one transgene-integration event on mouse chromosome 10.…”

Section: Mglu1 In Melanomasupporting

confidence: 58%

Role of the G Protein-Coupled Receptor, mGlu1, in Melanoma Development

2010

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Melanoma remains one of the cancers for which a decline in morbidity has not been achieved with current scientific and medical advances. Mono-therapies targeting melanoma have been largely ineffective, increasing the need for identification of new drugable targets. Multiple tumor suppressors and oncogenes that impart genetic predisposition to melanoma have been identified and are being studied in an attempt to provide insight on the development of anti-melanoma therapies. Metabotropic Glutamate Receptor I (GRM1) has recently been implicated as a novel oncogene involved in melanomagenesis. GRM1 (mGlu1, protein) belongs to the G protein coupled receptor (GPCR) super family and is normally functional in the central nervous system. Our group showed in a transgenic mouse model system that ectopic expression of Grm1 in melanocytes is sufficient to induce spontaneous melanoma development in vivo. GPCRs are some of the most important therapeutic drug targets discovered to date and they make up a significant proportion of existing therapies. This super family of transmembrane receptors has wide spread expression and interacts with a diverse array of ligands. Diverse physiological responses can be induced by stimulator(s) or suppressor(s) of GPCRs, which contributes to their attractiveness in existing and emerging therapies. GPCR targeting therapies are employed against a variety of human disorders including those of the central nervous system, cardiovascular, metabolic, urogenital and respiratory systems. In the current review, we will discuss how the identification of the oncogenic properties of GRM1 opens up new strategies for the design of potential novel therapies for the treatment of melanoma.

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Section: Mglu1 In Melanomasupporting

confidence: 58%

Role of the G Protein-Coupled Receptor, mGlu1, in Melanoma Development

2010

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“…Previous studies have implicated mGluR1 in melanoma (21,29), but, until now, there was no evidence of a similar role for mGluR5. The studies on mGluR1 and melanoma began with the characterization of an insertional mouse mutant line, TG3, that was predisposed to develop multiple melanomas affecting the pinnae of the ear, perianal reion, eyelid, snout, trunk, and legs (30)(31)(32). Physical mapping of this TG3 line revealed that intron 3 of the Grm1 (mGluR1) gene was affected and resulted in aberrant expression of mGluR1 in skin tissues (21).…”

Section: Discussionmentioning

confidence: 99%

Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice

Choi

Chang

Pickel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Glutamate is the major excitatory neurotransmitter in the mammalian CNS and mediates fast synaptic transmission upon activation of glutamate-gated ion channels. In addition, glutamate modulates a variety of other synaptic responses and intracellular signaling by activating metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors. The mGluRs are also expressed in nonneuronal tissues and are implicated in a variety of normal biological functions as well as diseases. To study mGluR-activated calcium signaling in neurons, we generated mGluR5 transgenic animals using a Thy1 promoter to drive expression in the forebrain, and one founder unexpectedly developed melanoma. To directly investigate the role of mGluR5 in melanoma formation, we generated mGluR5 transgenic lines under a melanocyte-specific promoter, tyrosinase-related protein 1. A majority of the founders showed a severe phenotype with early onset. Hyperpigmentation of the pinnae and tail could be detected as early as 3-5 d after birth for most of the mGluR5 transgene-positive mice. There was 100% penetrance in the progeny from the tyrosinase-related protein 1-mGluR5 lines generated from founders that developed melanoma. Expression of mGluR5 was detected in melanoma samples by RT-PCR, immunoblotting, and immunohistochemistry. We evaluated the expression of several cancer-related proteins in tumor samples and observed a dramatic increase in the phosphorylation of ERK, implicating ERK as a downstream effector of mGluR5 signaling in tumors. Our findings show that mGluR5-mediated glutamatergic signaling can trigger melanoma in vivo. The aggressive growth and severe phenotype make these mouse lines unique and a potentially powerful tool for therapeutic studies.etabotropic glutamate receptors (mGluRs) are G proteincoupled receptors that are widely expressed in the brain and modulate many diverse signaling pathways. In the CNS, mGluR activation regulates ion channels, mediates slow excitatory and inhibitory responses, modulates neurotransmitter release, and regulates neuronal development and growth (1-3). In addition, various neurological disorders have been attributed to functional impairment of mGluRs in the CNS. The mGluRs (mGluR1-8) are classified into three groups on the basis of sequence identity and pharmacological properties. Group I mGluRs (mGluR1 and mGluR5) are G q -coupled receptors that activate PLCβ, resulting in intracellular Ca 2+ release and protein kinase C (PKC) activation (4).Although glutamate signaling is usually investigated in the context of CNS function, it clearly plays a role in nonneuronal cells as well. In particular, glutamate signaling has been described in astrocytes, cerebral endothelial cells, bone, and skin (5, 6). In bone cells, glutamate or NMDA application increases NMDA receptor currents (7). Similarly, mGluR5 expression has been observed in many types of cells other than neurons, including astrocytes, hepatocytes, melanocytes, osteoblast cells (8-11), fibroblast cells (12), and more recently, stem cells ...

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“…Using a transgenic mouse model (2), our group identified that the ectopic expression of metabotropic glutamate receptor 1 ( Grm1 ), in melanocytes was sufficient to induce spontaneous melanoma development (3). Grm1 is a G-Protein coupled receptor whose expression is normally localized to the central and peripheral nervous system and has functional implications on learning and memory formation (4).…”

Section: Introductionmentioning

confidence: 99%

Functional Effects of GRM1 Suppression in Human Melanoma Cells

Wangari-Talbot

Wall

Goydos³

et al. 2012

Molecular Cancer Research

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Ectopic expression of a neuronal receptor, metabotropic glutamate receptor 1 (Grm1), in melanocytes has been implicated in melanoma development in mouse models. The human relevance of this receptor's involvement in melanoma pathogenesis was shown by detecting GRM1 expression in subsets of human melanomas, an observation lacking in benign nevi or normal melanocytes. Grm1-transformed mouse melanocytes and a conditional Grm1 transgenic mouse model confirmed a requirement for sustained expression of Grm1 for the maintenance of transformed phenotypes in vitro and tumorigenicity in vivo. Here, we investigate if continued GRM1 expression is also required in human melanoma cell lines by using two inducible, silencing RNA systems: the ecdysone/ Ponasterone A and tetracycline on/off approaches to regulate GRM1 expression in the presence of each inducer. Various in vitro assays were conducted to assess the consequences of a reduction in GRM1 expression on cell proliferation, apoptosis, downstream targeted signaling pathways, and in vivo tumorigenesis. We showed that suppression of GRM1 expression in several human melanoma cell lines resulted in a reduction in the number of viable cells and a decrease in stimulated mitogen-activated protein kinase (MAPK) and PI3K/AKT and suppressed tumor progression in vivo. These results reinforce earlier observations where a reduction in cell growth in vitro and tumorigenesis in vivo were correlated with decreased GRM1 activities by pharmacologic inhibitors of the receptor, supporting the notion that GRM1 plays a role in the maintenance of transformed phenotypes in human melanoma cells in vitro and in vivo and could be a potential therapeutic target for the treatment of melanoma.

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Development of Early Melanocytic Lesions in Transgenic Mice Predisposed to Melanoma

Cited by 21 publications

References 23 publications

Role of the G Protein-Coupled Receptor, mGlu1, in Melanoma Development

Role of the G Protein-Coupled Receptor, mGlu1, in Melanoma Development

Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice

Functional Effects of GRM1 Suppression in Human Melanoma Cells

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