Mirk protein kinase is a mitogen-activated protein kinase substrate that mediates survival of colon cancer cells.
Mirk protein kinase is a mitogen-activated protein kinase substrate that mediates survival of colon cancer cells.
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发表时间：
2000-07
期刊：
影响因子：
11.2
通讯作者：
K. Lee;X. Deng;E. Friedman
中科院分区：
文献类型：
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作者：
K. Lee;X. Deng;E. Friedman
我们已经克隆了一个新的基因mirk（minibrain-related kinase），它编码一种蛋白激酶，使结肠癌细胞能够在一定的应激条件下存活。Mirk是一种丝裂原活化蛋白激酶底物，但在体内被活化的细胞外信号调节激酶（erks）下调。Mirk包含一个PEST区域，其特征是快速转换蛋白质，并且仅在细胞核中被分解为Mr 57，000的形式。在三种结肠癌细胞系中，当ERK激活被MEK抑制剂PD 98059在无血清培养基中阻断时，mirk水平增加20倍。添加IGF-I以激活erks阻断了这种增加。Mirk在两种结肠癌细胞系中稳定过表达，达到结肠癌中可见的水平。5个mirk转染子中的每一个都在切换到无血清培养基时增殖，并且在血清恢复时恢复快速生长，而5个载体对照转染子和3个激酶死亡突变体mirk转染子则没有。在几种类型的癌中，mirk mRNA水平升高，并且在七种结肠癌细胞系中的每一种中检测到mirk蛋白。与配对的正常结肠组织相比，mirk在八种结肠癌中的三种的蛋白质印迹中以更高的蛋白质水平表达，这表明mirk在结肠癌的一个子集的进化中起作用。mirk在结肠癌中没有突变。Mirk可能在有丝分裂原缺乏的环境中或在许多自分泌生长因子被诱导之前的结肠癌发展早期介导肿瘤细胞存活。
We have cloned a novel gene mirk (minibrain-related kinase) encoding a protein kinase that enables colon carcinoma cells to survive under certain stress conditions. Mirk is a mitogen-activated protein kinase substrate but is down-regulated by activated extracellular signal-regulated kinases (erks) in vivo. Mirk contains a PEST region characteristic of rapidly turned over proteins and is broken down to a Mr 57,000 form only in the nucleus. In each of three colon carcinoma cell lines, mirk levels were increased 20-fold when erk activation was blocked by the MEK inhibitor PD98059 in serum-free medium. Addition of IGF-I to activate erks blocked this increase. Mirk was stably overexpressed in two colon carcinoma cell lines to attain levels seen in colon cancers. Each of five mirk transfectants proliferated when switched to serum-free medium and regained rapid growth when serum was restored, whereas five vector control transfectants and three kinase-dead mutant mirk transfectants did not. mirk mRNA levels were elevated in several types of carcinomas, and mirk protein was detected in each of seven colon carcinoma cell lines. mirk was expressed at a higher protein level in Western blots from three of eight colon cancers compared with paired normal colon tissue, suggesting that mirk plays a role in the evolution of a subset of colon cancers. mirk is not mutated in colon carcinomas. Mirk may mediate tumor cell survival in mitogen-poor environments or early in colon cancer development before many autocrine growth factors have been induced.