Melanoma incidence and mortality rate in European populations are increasing worldwide. Approximately 10% of melanomas occur in individuals with familial predisposition, but loci associated with susceptibility to multiple melanomas have yet to be identified. Spontaneous and induced mouse mutants are tools for uncovering new genes and pathways implicated in a particular disease. An insertional mutant, TG3, was generated by pronuclear injection with a 2-kb genomic fragment, clone B (Colon-Teicher, et al. (1993) Nucl. Acids Res. 21:2223-2228). The previously described TG3 line is predisposed to develop multiple melanomas primarily affecting the pinnae of the ear, perianal region, eyelid, snout, trunk and legs (Chen, et al. (1996) J. Invest. Dermatol. 106:1145-1150; Zhu, et al. (1998) J. Invest. Dermatol. 110:247-252). Metastases to distant organs are detected in some cases (Chen, et al. (1996) supra; Zhu, et al. (1998) supra). Melanoma susceptibility was found to be linked with the presence of the transgene.
Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system, and it can signal through a variety of glutamate receptors. Although once thought to be restricted to the central nervous system, glutamate signaling has been shown in a variety of non-neuronal tissues, including bone and skin (Skerry and Genever (2001) Trends Pharmacol. Sci. 22:174-181). There are two main categories of glutamate receptors. The ionotropic receptors are glutamate-gated, cation-specific ion channels, whereas the metabotropic receptors are coupled to intracellular signal-transduction pathways through G proteins. Metabotropic glutamate receptors are members of the large family of seven-transmembrane-domain G protein-coupled receptors. Both Grm1 and Grm5 (also called Gprc1 and mgluR5) are group 1 metabotropic glutamate receptors coupling primarily to phosphoinositide hydrolysis. Grm1 has also been shown to couple to multiple intracellular signaling cascades including adenylate cyclase activation (Hermans and Chaliss (2001) Biochem. J. 359:465-484). Mice carrying null mutations in Grm1 have severe deficits in motor coordination and spatial learning (Aiba, et al. (1994) Cell 79:377-388; Aiba, et al. (1994) Cell 79:365-375; Conquet, et al. (1994) Nature 372:237-243), but no melanocyte defect has been described. Metabotropic glutamate receptors have not previously been implicated in tumorigenesis; however, a variety of G protein-coupled receptors and G proteins, including those that signal through phosphoinositide hydrolysis and cAMP accumulation, have been implicated in tumorigenesis through either mutational activation or overexpression (Dhanasekaran, et al. (1995) Endocr. Rev. 16:259-2701; Gutkind (1998) Oncogene 17:1331-1342). In addition, glutamate has been linked to tumor growth in both neuronal and non-neuronal cancers (Takano, et al. (2001) Nat. Med. 7:1010-1015; Rzeski, et al. (2001) Proc. Natl. Acad. Sci. USA 98:6372-6377). Further, glutamate has been shown to stimulate proliferation of lung carcinoma cells in serum-deprived media, and antagonists to the ionotropic glutamate receptors, AMPA and NMDA receptors, have been shown to inhibit proliferation and increase cell death in a calcium-dependent manner in a variety of non-neuronal cancers (Rzeski, et al. (2001) supra). Agonist stimulation of Grm5 in subconfluent melanocyte culture has also been shown to result in melanocyte proliferation (Frati, et al. (2000) J. Cell. Physiol. 183:364-372).
U.S. Pat. No. 5,869,609 teaches the identification, isolation and purification of Grm1. This reference further discloses anti-Grm1 antibodies for use in identifying agonists and antagonists of Grm1-mediated neuronal excitation, as well as in methods of diagnosis and/or treatment of diseases such as, for example, cerebral ischemia, Parkinsons, senile dementia and other cognitive disorders, Huntington's chorea, amyotrophic lateral sclerosis, emesis, and migraine. This reference does not teach a role for Grm1 in the development of melanocytic neoplasms.
U.S. Pat. No. 6,084,084 discloses a human metabotropic glutamate receptor 8 (mGluR8) protein and an immunoassay in which an antibody to mGluR8 is used to identify the number and/or location and/or functional integrity of mGluR8 or the presence of a cancer, e.g., an ectopic tumor of the central nervous system or peripheral nervous system. This reference does not disclose how mGluR8 is altered in a tumor cell nor does it teach the unscheduled expression of a glutamate receptor in malignant melanoma.
USPTO Backgrounds
USPTO Backgrounds