Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice
Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice
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DOI：
10.1073/pnas.1107304108
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发表时间：
2011-09-13
影响因子：
11.1
通讯作者：
Roche, Katherine W.
中科院分区：
文献类型：
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作者：
Choi, Kyu Yeong;Chang, Kai;Roche, Katherine W.
谷氨酸是哺乳动物中枢神经系统中主要的兴奋性神经递质，在谷氨酸门控离子通道激活后介导快速突触传递。此外，谷氨酸通过激活代谢型谷氨酸受体（mGluR）（G蛋白偶联受体）调节多种其他突触反应和细胞内信号传导。mGluRs也在非神经元组织中表达，并且与多种正常生物学功能以及疾病有关。为了研究神经元中mGluR激活的钙信号，我们使用Thy 1启动子来驱动前脑中的表达，产生了mGluR 5转基因动物，其中一个创始人意外地患上了黑色素瘤。为了直接研究mGluR 5在黑色素瘤形成中的作用，我们在黑色素细胞特异性启动子酪氨酸酶相关蛋白1下产生了mGluR 5转基因株系。大多数创始人表现出早期发病的严重表型。大多数mGluR 5转基因阳性小鼠在出生后3-5 d即可检测到尾鳍和尾部的色素沉着。酪氨酸酶相关蛋白1-mGluR 5系的后代中有100%的突变率，这些细胞系是由发展为黑素瘤的创始人产生的。通过RT-PCR、免疫印迹和免疫组化检测黑色素瘤样品中mGluR 5的表达。我们评估了肿瘤样本中几种癌症相关蛋白的表达，并观察到ERK磷酸化的显著增加，表明ERK是肿瘤中mGluR 5信号传导的下游效应子。我们的研究结果表明，mGluR 5介导的谷氨酸能信号可以触发体内黑色素瘤。侵袭性生长和严重的表型使这些小鼠品系独特，并成为治疗研究的潜在有力工具。
Glutamate is the major excitatory neurotransmitter in the mammalian CNS and mediates fast synaptic transmission upon activation of glutamate-gated ion channels. In addition, glutamate modulates a variety of other synaptic responses and intracellular signaling by activating metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors. The mGluRs are also expressed in nonneuronal tissues and are implicated in a variety of normal biological functions as well as diseases. To study mGluR-activated calcium signaling in neurons, we generated mGluR5 transgenic animals using a Thy1 promoter to drive expression in the forebrain, and one founder unexpectedly developed melanoma. To directly investigate the role of mGluR5 in melanoma formation, we generated mGluR5 transgenic lines under a melanocyte-specific promoter, tyrosinase-related protein 1. A majority of the founders showed a severe phenotype with early onset. Hyperpigmentation of the pinnae and tail could be detected as early as 3-5 d after birth for most of the mGluR5 transgene-positive mice. There was 100% penetrance in the progeny from the tyrosinase-related protein 1-mGluR5 lines generated from founders that developed melanoma. Expression of mGluR5 was detected in melanoma samples by RT-PCR, immunoblotting, and immunohistochemistry. We evaluated the expression of several cancer-related proteins in tumor samples and observed a dramatic increase in the phosphorylation of ERK, implicating ERK as a downstream effector of mGluR5 signaling in tumors. Our findings show that mGluR5-mediated glutamatergic signaling can trigger melanoma in vivo. The aggressive growth and severe phenotype make these mouse lines unique and a potentially powerful tool for therapeutic studies.