Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia
| Autor: | Suzie Chen, Pamela M. Pollock, Jeffrey J. Martino, Raman Sood, Karen J. Dunn, Kerine R. Mackason, James S. Goydos, Christiane M. Robbins, Kevin Ryan, William J. Pavan, Michael Eckhaus, Steven M. Crespo-Carbone, Christopher L. Graham, Yarí E. Marín, Jun Cheng, Daniel Sinsimer, Jin Namkoong, Arturo Incao, Kenneth R. Reuhl, Jeffrey M. Trent, Izabela Makalowska, Amy Chen, Kathleen G. Roberts, Laura M. Yudt, Aruna Koganti, Heather W. Pinkett, Paul S. Meltzer, Seung Shick Shin, Hua Zhu, Karine A. Cohen-Solal |
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| Rok vydání: | 2002 |
| Předmět: |
Genetically modified mouse
DNA Complementary Skin Neoplasms Transgene Molecular Sequence Data Mice Transgenic Biology Receptors Metabotropic Glutamate Transfection Insertional mutagenesis Mice Genetics medicine Animals Melanoma Regulation of gene expression DNA Neoplasm medicine.disease Gene Expression Regulation Neoplastic Mice Inbred C57BL Mutagenesis Insertional Cancer research Metabotropic glutamate receptor 1 Signal transduction Dopachrome tautomerase Signal Transduction |
| Zdroj: | Nature genetics. 34(1) |
| ISSN: | 1061-4036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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