Hui Lijian, Bakiri Latifa, Mairhorfer Andreas, Schweifer Norbert, Haslinger Christian, Kenner Lukas, Komnenovic Vukoslav, Scheuch Harald, Beug Hartmut, Wagner Erwin F
Research Institute of Molecular Pathology, A-1030 Vienna, Austria.
Nat Genet. 2007 Jun;39(6):741-9. doi: 10.1038/ng2033. Epub 2007 Apr 29.
The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) 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 p38alpha 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 p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development.
丝裂原活化蛋白激酶（MAPK）p38α控制炎症反应和细胞增殖。我们利用携带条件性Mapk14（也称为p38α）等位基因的小鼠，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删除Mapk14时，胎儿能够足月发育，但出生后不久死亡，可能是由于肺功能障碍。缺乏p38α的胎儿造血细胞和胚胎成纤维细胞由于c-Jun氨基末端激酶（JNK）-c-Jun途径的持续激活而显示出增殖增加。值得注意的是，在化学诱导的肝癌发生过程中，肝脏特异性删除Mapk14的小鼠表现出增强的肝细胞增殖和肿瘤发展，这与JNK-c-Jun途径的上调相关。此外，JNK或c-Jun的失活抑制了Mapk14缺陷型肝细胞和肿瘤细胞的增殖增加。这些结果证明了一种新机制，即p38α通过在多种细胞类型和肝癌发生过程中拮抗JNK-c-Jun途径来负向调节细胞增殖。
