Pollock Pamela M, Cohen-Solal Karine, Sood Raman, Namkoong Jin, Martino Jeffrey J, Koganti Aruna, Zhu Hua, Robbins Christiane, Makalowska Izabela, Shin Seung-Shick, Marin Yari, Roberts Kathleen G, Yudt Laura M, Chen Amy, Cheng Jun, Incao Arturo, Pinkett Heather W, Graham Christopher L, Dunn Karen, Crespo-Carbone Steven M, Mackason Kerine R, Ryan Kevin B, Sinsimer Daniel, Goydos James, Reuhl Kenneth R, Eckhaus Michael, Meltzer Paul S, Pavan William J, Trent Jeffrey M, Chen Suzie
Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Genet. 2003 May;34(1):108-12. doi: 10.1038/ng1148.
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.
为深入了解黑色素瘤的发病机制，我们对一种插入型小鼠突变体TG3进行了特征分析，该突变体易发生多发性黑色素瘤。物理图谱分析确定转基因在Grm1（编码代谢型谷氨酸受体1）的内含子3中存在多个串联插入，同时有70 kb的内含子序列缺失。为评估这种插入诱变事件是否导致转录调控改变，我们分析了Grm1和两个侧翼基因在TG3小鼠黑色素瘤中的异常表达情况。我们仅观察到Grm1的异常表达。尽管在正常小鼠黑素细胞中未检测到其表达，但Grm1在TG3小鼠的黑色素瘤中异位表达。为证实Grm1参与黑素细胞肿瘤形成，我们构建了另一个转基因品系，其Grm1表达由多巴色素互变异构酶启动子驱动。与原始的TG3相似，Tg(Grm1)EPv品系易患黑色素瘤。与人类黑色素瘤不同，这些转基因小鼠黑素细胞普遍过度增殖，向完全恶性转移的转化有限。我们在一些人类黑色素瘤活检组织和细胞系中检测到GRM1的表达，但在良性痣和黑素细胞中未检测到。这项研究为代谢型谷氨酸信号在黑素细胞肿瘤形成中的重要性提供了有力证据。
