Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors
Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors
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DOI：
10.1158/0008-5472.can-08-1467
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
May, W. Stratford, Jr.
中科院分区：
文献类型：
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作者：
Hoare, Sarasiia;Hoare, Kishalay;May, W. Stratford, Jr.
Tnk1/kos1是一种非受体蛋白酪氨酸激酶，在一种需要其内在催化活性的机制中参与负调控细胞生长。通过删除催化结构域的同源重组，建立Tnk1/Kos1缺失小鼠。Tnk1(+/-)和Tnk1(-/-)小鼠的自发肿瘤发生率都很高[分别为27%(14/52)和43%(12/28)]，包括淋巴瘤和癌症。在Tnk1(+/-)小鼠发生的肿瘤中，Tnk1/Kos1的表达被沉默，但在邻近未受影响的组织中不表达，沉默发生与Tnk1启动子的高甲基化有关。来自Tnk1/Kos1缺失小鼠的组织和小鼠胚胎成纤维细胞表现出比例更高的基础和表皮生长因子刺激的RAS激活，这是由于RAS-鸟嘌呤交换因子(Global)活性增加所致。从机制上讲，Tnk1/Kos1可以直接酪氨酸磷酸化生长因子受体结合蛋白2(Grb2)，促进Grb2-Sos1复合体的破坏，从而通过抑制RAS来动态调节RAS环境基金的活性。因此，Tnk1/Kos1是一种肿瘤抑制因子，其功能是下调RAS活性。
Tnk1/Kos1 is a non-receptor protein tyrosine kinase implicated in negatively regulating cell growth in a mechanism requiring its intrinsic catalytic activity. Tnk1/Kos1 null mice were created by homologous recombination by deleting the catalytic domain. Both Tnk1(+/-) and Tnk1(-/-) mice develop spontaneous tumors, including lymphomas and carcinomas, at high rates [27% (14 of 52) and 43% (12 of 28), respectively]. Tnk1/Kos1 expression is silenced in tumors that develop in Tnk1(+/-) mice but not in adjacent uninvolved tissue, and silencing occurs in association with Tnk1 promoter hypermethylation. Tissues and murine embryonic fibroblasts derived from Tnk1/Kos1-null mice exhibit proportionally higher levels of basal and epidermal growth factor-stimulated Ras activation that results from increased Ras-guanine exchange factor (GEF) activity. Mechanistically, Tnk1/Kos1 can directly tyrosine phosphorylate growth factor receptor binding protein 2 (Grb2), which promotes disruption of the Grb2-Sos1 complex that mediates growth factor-induced Ras activation, providing dynamic regulation of Ras GEF activity with suppression of Ras. Thus, Tnk1/Kos1 is a tumor suppressor that functions to down-regulate Ras activity.