title: Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia.
abstract: To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas. 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.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Pollock
authors.forename: Karine
authors.initials: K
authors.lastname: Cohen-Solal
authors.forename: Raman
authors.initials: R
authors.lastname: Sood
authors.forename: Jin
authors.initials: J
authors.lastname: Namkoong
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Martino
authors.forename: Aruna
authors.initials: A
authors.lastname: Koganti
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.forename: Christiane
authors.initials: C
authors.lastname: Robbins
authors.forename: Izabela
authors.initials: I
authors.lastname: Makalowska
authors.forename: Seung-Shick
authors.initials: SS
authors.lastname: Shin
authors.forename: Yari
authors.initials: Y
authors.lastname: Marin
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Roberts
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yudt
authors.forename: Amy
authors.initials: A
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Arturo
authors.initials: A
authors.lastname: Incao
authors.forename: Heather W
authors.initials: HW
authors.lastname: Pinkett
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Graham
authors.forename: Karen
authors.initials: K
authors.lastname: Dunn
authors.forename: Steven M
authors.initials: SM
authors.lastname: Crespo-Carbone
authors.forename: Kerine R
authors.initials: KR
authors.lastname: Mackason
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Ryan
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinsimer
authors.forename: James
authors.initials: J
authors.lastname: Goydos
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Reuhl
authors.forename: Michael
authors.initials: M
authors.lastname: Eckhaus
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.forename: Suzie
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D004273:DNA, Neoplasm; D018094:Receptors, Metabotropic Glutamate