Grg1 acts as a lung-specific oncogene in a transgenic mouse model
Grg1 acts as a lung-specific oncogene in a transgenic mouse model
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DOI：
10.1158/0008-5472.can-05-1634
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Lobe, CG
中科院分区：
文献类型：
--
作者：
Allen, T;van Tuyl, M;Lobe, CG
Groucho蛋白是一种转录辅阻遏物，被许多转录因子募集到基因调控区。长的同种型，如Grg 1，具有果蝇Groucho原型的所有结构域。短格劳乔蛋白，如Grg 5，只有氨基末端的Q和G/P结构域。我们产生了Grg 1和Grg 5转基因小鼠，发现Grg 1过表达诱导肺腺癌，而Grg 5过表达不会。Grg 5与Grg 1的共表达降低了肿瘤负荷。Grg 1和Grg 5均降低p53蛋白水平;然而，仅Grg 1过表达诱导ErbB 1和ErbB 2受体酪氨酸激酶水平升高。在Grgl转基因小鼠中伴随肿瘤进展的分子和生物学变化密切重申了在人肺癌中观察到的事件。我们还发现，在人肺肿瘤组织阵列中，大量癌细胞过度表达Grg 1/TLE 1。我们的数据表明，Grg 1过度表达有助于人类肺癌的恶性程度。
Groucho proteins are transcriptional corepressors that are recruited to gene regulatory regions by numerous transcription factors. Long isoforms, such as Grg1, have all the domains of the prototype Drosophila Groucho. Short Groucho proteins, such as Grg5, have only the amino-terminal Q and G/P domains. We generated Grg1 and Grg5 transgenic mice and found that Grg1 overexpression induces lung adenocarcinoma, whereas Grg5 overexpression does not. Coexpression of Grg5 with Grg1 reduces tumor burden. Grg1 and Grg5 both diminish p53 protein levels; however, only Grgl overexpression induces elevated levels of ErbB1 and ErbB2 receptor tyrosine kinases. The molecular and biological changes that accompany tumor progression in Grgl transgenic mice closely reiterate events seen in human lung cancer. We also found that within a human lung tumor tissue array, a significant number of carcinomas overexpress Grg1/TLE1. Our data suggest that Grg1 overexpression contributes to malignancy in human lung cancers.