Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia
Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia
复制标题
DOI：
10.1038/ng1148
复制
发表时间：
2003-05-01
期刊：
影响因子：
30.8
通讯作者：
Chen, S
中科院分区：
文献类型：
--
作者：
Pollock, PM;Cohen-Solal, K;Chen, S
为了深入了解黑色素瘤发病机制，我们表征了一种插入小鼠突变体TG3，其易于发生多发性黑色素瘤（1，2）。物理作图确定了多个串联插入的转基因到内含子3的Grm1（编码代谢型谷氨酸受体1）伴随着删除70 kb的内含子序列。为了评估这种插入突变事件是否会导致转录调控的改变，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。我们只观察到Grm1的异常表达。虽然我们没有检测到它在正常小鼠黑素细胞中的表达，Grm1异位表达在黑色素瘤从TG3小鼠。为了证实Grm1参与黑素细胞瘤形成，我们创建了一个额外的转基因株系，其表达由多巴色素互变异构酶启动子驱动。与原始TG3相似，Tg（Grm1）EPv系对黑色素瘤易感。与人黑色素瘤相反，这些转基因小鼠具有黑色素细胞的普遍过度增殖，具有有限的转化为完全恶性转移。我们检测到GRM1的表达在一些人类黑色素瘤活检和细胞系，但不是在良性痣和黑色素细胞。这项研究为代谢型谷氨酸信号在黑素细胞瘤中的重要性提供了令人信服的证据。
To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas(1,2). 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.