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Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia

Pollock, P.M., Cohen-Solal, K., Sood, R., Namkoong, J., Martino, J.J., Koganti, A., Zhu, H., Robbins, C., Makalowska, I., Shin, S.S., Marin, Y., Roberts, K.G., Yudt, L.M., Chen, A., Cheng, J., Incao, A., Pinkett, H.W., Graham, C.L., Dunn, K., Crespo-Carbone, S.M., Mackason, K.R., Ryan, K.B., Sinsimer, D., Goydos, J., Reuhl, K.R., Eckhaus, M., Meltzer, P.S., Pavan, W.J., Trent, J.M., & Chen, S. (2003) Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nature Genetics, 34(1), pp. 108-112.

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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.

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124 citations in Web of Science®

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ID Code: 45823
Item Type: Journal Article
Keywords: Animals, DNA, Complementary/genetics, DNA, Neoplasm/genetics, Gene Expression Regulation, Neoplastic, Melanoma/ genetics/ metabolism/pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Mutagenesis, Insertional, Receptors, Metabotropic Glutamate/ genetics/ metabolism, Signal Transduction, Skin Neoplasms/ genetics/ metabolism/pathology, Transfection
DOI: 10.1038/ng1148
ISSN: 1061-4036
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Divisions: Past > Schools > Cell & Molecular Biosciences
Past > QUT Faculties & Divisions > Faculty of Science and Technology
Past > Institutes > Institute for Sustainable Resources
Deposited On: 15 Sep 2011 16:04
Last Modified: 15 Sep 2011 16:04

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