title: Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice.
abstract: 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.
authors: Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Kyu Yeong
authors: KY
authors: Choi
authors: Kai
authors: K
authors: Chang
authors: James M
authors: JM
authors: Pickel
authors: John D
authors: JD
authors: Badger
authors: Katherine W
authors: KW
authors: Roche
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D019042:Muscle Neoplasms / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D010858:Pigmentation; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012878:Skin Neoplasms / Q000201:enzymology / Q000473:pathology
chemical_list: C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D048049:Extracellular Signal-Regulated MAP Kinases