p38α suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway
p38α suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway
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DOI：
10.1038/ng2033
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发表时间：
2007-06-01
期刊：
影响因子：
30.8
通讯作者：
Wagner, Erwin F.
中科院分区：
文献类型：
--
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
丝裂原活化蛋白激酶（MAPK）p38 a控制炎症反应和细胞增殖。使用携带条件性Mapk 14（也称为p38 a）等位基因的小鼠，我们研究了其在出生后发育和肿瘤发生中的功能。当我们在小鼠胚胎中特异性地删除Mapk 14时，胎儿发育到足月，但出生后不久就死亡了，可能是由于肺功能障碍。胎儿造血细胞和胚胎成纤维细胞缺乏p38 a表现出增加的增殖，导致持续激活的c-Jun N-末端激酶（JNK）-c-Jun途径。值得注意的是，在化学诱导的肝癌发展中，Mapk 14肝脏特异性缺失的小鼠显示出与JNK-c-Jun通路上调相关的肝细胞增殖和肿瘤发展增强。此外，JNK或c-Jun的失活抑制Mapk 14缺陷肝细胞和肿瘤细胞的增殖增加。这些结果证明了一种新的机制，即p38 a通过拮抗多种细胞类型和肝癌发展中的JNK-c-Jun途径来负调控细胞增殖。
yThe mitogen-activated protein kinase (MAPK) p38a controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 ( also known as p38a) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38a showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK-c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38a negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development.