While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable
While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable
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DOI：
10.1128/mcb.23.24.9245-9250.2003
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发表时间：
2003-12-01
影响因子：
5.3
通讯作者：
Patek, CE
中科院分区：
文献类型：
--
作者：
Plowman, SJ;Williamson, DJ;Patek, CE
在哺乳动物中，三种经典ras基因编码四种高度同源的蛋白，N-Ras、H-Ras以及K-Ras 4A和4B同工型。既往研究表明，K-ras对小鼠发育至关重要，K-ras 4A和4B在发育过程中表达，而K-ras 4A的表达受时间和空间调控，在成人肾、肠、胃和肝脏均有表达。在本研究中，我们在广泛的野生型成年小鼠组织中检测了K-ras 4A的表达模式，并采用基因靶向的方法产生K-ras 4A缺陷小鼠，以研究其在发育中的作用。发现K-ras 4A在子宫、肺、胰腺、唾液腺、精囊、骨髓细胞和盲肠中也有表达，是主要的K-ras亚型。K-ras（tmDelta4A/+）小鼠之间的交配产生了具有预期孟德尔遗传比的存活的K-ras（tmDelta4A/tmDelta4A）后代，这些小鼠仅表达K-ras 4B剪接变体。K-ras（tm-Delta4A/t-Delta4A）小鼠在近交（129/Ola）或杂交（129/Ola x C57BL/6）遗传背景下均可生育，无组织病理学异常。结果表明，K-Ras 4A与H- ras和N-Ras一样，在正常小鼠发育中是必不可少的，至少在功能性K-Ras 4B存在的情况下是如此。
In mammals, the three classical ras genes encode four highly homologous proteins, N-Ras, H-Ras, and the isoforms K-Ras 4A and 4B. Previous studies have shown that K-ras is essential for mouse development and that while K-ras 4A and 4B are expressed during development, K-ras 4A expression is regulated temporally and spatially and occurs in adult kidney, intestine, stomach, and liver. In the present study, the pattern of K-ras 4A expression was examined in a wide range of wild-type adult mouse tissues, and gene targeting was used to generate K-ras 4A-deficient mice to examine its role in development. It was found that K-ras 4A is also expressed in uterus, lung, pancreas, salivary glands, seminal vesicles, bone marrow cells, and cecum, where it was the major K-Ras isoform expressed. Mating between K-ras(tmDelta4A/+) mice produced viable K-ras(tmDelta4A/tmDelta4A) offspring with the expected Mendelian ratios of inheritance, and these mice expressed the K-ras 4B splice variant only. K-ras(tm-Delta4A/t-Delta4A) mice were fertile and showed no histopathological abnormalities on inbred (129/Ola) or crossbred (129/Ola x C57BL/6) genetic backgrounds. The results demonstrate that K-Ras 4A, like H- and N-Ras, is dispensable for normal mouse development, at least in the presence of functional K-Ras 4B.