Receptor for activated C kinase 1 promotes hepatocellular carcinoma growth by enhancing mitogen-activated protein kinase kinase 7 activity
Receptor for activated C kinase 1 promotes hepatocellular carcinoma growth by enhancing mitogen-activated protein kinase kinase 7 activity
复制标题
活化 C 激酶 1 的受体通过增强丝裂原活化蛋白激酶激酶 7 活性来促进肝细胞癌生长。
DOI：
10.1002/hep.25978
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发表时间：
2013-01-01
期刊：
影响因子：
13.5
通讯作者：
Zhang, Jiyan
中科院分区：
文献类型：
--
作者：
Guo, Yuanyuan;Wang, Wendie;Zhang, Jiyan
c-Jun N-末端蛋白激酶（JNK）是丝裂原活化蛋白激酶（MAPK）超家族的成员。JNK的激活是通过MAPK模块，即MAPK激酶（MAP 3 K或MEKK）的顺序蛋白磷酸化介导的？MAPK激酶（MAP 2K或MKK）？MAPK。JNK活性水平的升高在肝细胞癌（HCC）中经常被观察到，并且已被证明通过促进HCC细胞增殖和对肿瘤坏死因子相关凋亡诱导配体（TRAIL）或Fas介导的凋亡的抵抗而促进HCC生长。慢性炎症导致HCC中JNK活性上调。然而，仍然不清楚异常的JNK活性是否也是由某些细胞内在缺陷引起的。在这里，我们表明，受体活化C激酶1（RACK 1），一个衔接蛋白参与多种信号通路的调节，可以从事与MKK 7，JNK特异性的MAP 2K，在人肝癌细胞中的直接相互作用。RACK 1蛋白水平与人HCC组织和细胞系中JNK通路的活性相关。RACK 1功能丧失或功能获得分析表明，RACK 1增强人HCC细胞中的MKK 7/JNK活性。进一步的研究表明，RACK 1与MKK 7的相互作用是RACK 1增强MKK 7/JNK活性所必需的。RACK 1/MKK 7相互作用促进MKK 7与MAP 3 Ks的结合，从而增强MKK 7活性并促进体外HCC细胞增殖和对TRAIL或Fas介导的凋亡的抗性以及体内肿瘤生长。结论：RACK 1过表达可增强JNK活性，通过与MKK 7直接结合，增强MKK 7活性，从而促进肝癌的生长。（肝脏学2013; 57：140-151）
c-Jun N-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) superfamily. The activation of JNK is mediated by sequential protein phosphorylation through a MAPK module, namely, MAPK kinase kinase (MAP3K or MEKK) ? MAPK kinase (MAP2K or MKK) ? MAPK. Elevated levels of JNK activity have been frequently observed in hepatocellular carcinoma (HCC) and have been demonstrated to contribute to HCC growth by promoting HCC cell proliferation and resistance to tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL)- or Fas-mediated apoptosis. Chronic inflammation contributes to the up-regulation of JNK activity in HCC. However, it remains unknown whether aberrant JNK activity also results from some cell intrinsic defect(s). Here, we show that receptor for activated C kinase 1 (RACK1), an adaptor protein implicated in the regulation of multiple signaling pathways, could engage in a direct interaction with MKK7, the JNK-specific MAP2K, in human HCC cells. Levels of RACK1 protein show correlation with the activity of the JNK pathway in human HCC tissues and cell lines. RACK1 loss-of-function or gain-of-function analyses indicate that RACK1 enhances MKK7/JNK activity in human HCC cells. Further exploration reveals that the interaction of RACK1 with MKK7 is required for the enhancement of MKK7/JNK activity by RACK1. RACK1/MKK7 interaction facilitates the association of MKK7 with MAP3Ks, thereby enhancing MKK7 activity and promoting in vitro HCC cell proliferation and resistance to TRAIL- or Fas-mediated apoptosis as well as in vivo tumor growth. Conclusion: Overexpressed RACK1 augments JNK activity and thereby promotes HCC growth through directly binding to MKK7 and enhancing MKK7 activity. (HEPATOLOGY 2013; 57: 140-151)