Nature Genetics
34, 108 - 112 (2003)
Published online: 21 April 2003; | doi:10.1038/ng1148
Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasiaPamela M. Pollock1, 9, Karine Cohen-Solal2, 9, Raman Sood1, 9, Jin Namkoong2, Jeffrey J. Martino2, Aruna Koganti2, Hua Zhu2, Christiane Robbins1, Izabela Makalowska3, Seung-Shick Shin2, Yari Marin2, Kathleen G. Roberts4, Laura M. Yudt1, Amy Chen5, Jun Cheng5, Arturo Incao5, Heather W. Pinkett1, Christopher L Graham1, Karen Dunn5, Steven M. Crespo-Carbone2, Kerine R. Mackason2, Kevin B. Ryan2, Daniel Sinsimer2, James Goydos6, 7, Kenneth R. Reuhl4, Michael Eckhaus8, Paul S. Meltzer1, William J. Pavan5, Jeffrey M. Trent1
& Suzie Chen2, 71
Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. 2
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA. 3
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. 4
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA. 5
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. 6
Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA. 7
The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA. 8
Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892, USA. 9
These authors contributed equally to this work.
Correspondence should be addressed to Suzie Chen suziec@rci.rutgers.eduTo gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas1,
2. Physical mapping identified multiple tandem insertions of the transgene into intron 3 of Grm1 (encoding metabotropic glutamate receptor 1) with concomitant deletion of 70 kb of intronic sequence. To assess whether this insertional mutagenesis event results in alteration of transcriptional regulation, we analyzed Grm1 and two flanking genes for aberrant expression in melanomas from TG3 mice. We observed aberrant expression of only Grm1. Although we did not detect its expression in normal mouse melanocytes, Grm1 was ectopically expressed in the melanomas from TG3 mice. To confirm the involvement of Grm1 in melanocytic neoplasia, we created an additional transgenic line with Grm1 expression driven by the dopachrome tautomerase promoter. Similar to the original TG3, the Tg(Grm1)EPv line was susceptible to melanoma. In contrast to human melanoma, these transgenic mice had a generalized hyperproliferation of melanocytes with limited transformation to fully malignant metastasis. We detected expression of GRM1 in a number of human melanoma biopsies and cell lines but not in benign nevi and melanocytes. This study provides compelling evidence for the importance of metabotropic glutamate signaling in melanocytic neoplasia.
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