Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease
Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease
复制标题
DOI：
10.1016/s0002-9440(10)62231-6
复制
发表时间：
2005-01-01
影响因子：
6
通讯作者：
Nakanuma, Y
中科院分区：
文献类型：
--
作者：
Sato, Y;Harada, K;Nakanuma, Y
多囊肾(PCK)大鼠表现出类似人类常染色体隐性遗传性多囊肾病的多器官囊性病变，被认为是Caroli病合并先天性肝纤维化(CHF)的动物模型。本研究探讨了丝裂原活化蛋白激酶(MAPK)通路部分组分在体外培养的PCK大鼠肝内胆管上皮细胞(BECs)中的表达和功能。与对照组相比，PCK组大鼠培养的BECs对表皮生长因子(EGF)具有高反应性。BEC的增殖增加伴随着MAPK/细胞外信号调节蛋白激酶5(MEK5)的过度表达以及随后的ERK5的磷酸化。针对MEK5基因的短干扰RNA可显著抑制细胞增殖活性的增强。EGF受体酪氨酸激酶抑制剂吉非替尼(“易瑞沙”，ZD1839)也能显著抑制PCK大鼠培养的BECs的异常生长。相比之下，MEK1/2的抑制剂PD98059和U0126的治疗效果较差。这些结果提示，MEK5-ERK5级联激活在PCK大鼠胆道发育不良中起着关键作用，也为探讨Caroli病合并CHF的发病机制提供了新的思路。由于MEK5-ERK5的相互作用具有高度的特异性，它可能是一个潜在的治疗靶点。
Polycystic kidney (PCK) rats exhibit a multiorgan cyst pathology similar to human autosomal recessive polycystic kidney disease, and are proposed as an animal model of Caroli's disease with congenital hepatic fibrosis (CHF). This study investigated the expression and function of selected components of the mitogen activated protein kinase (MAPK) pathway in cultured intrahepatic biliary epithelial cells (BECs) of PCK rats. Compared to the proliferative activity of cultured BECs of control rats, those of the PCK rats were hyperresponsive to epidermal growth factor (EGF). The increase in BEC proliferation was accompanied by overexpression of MAPK/extracellular signal-regulated protein kinase (ERK) kinase 5 (MEK5), and subsequent phosphorylation of ERK5 in vitro. The increased proliferative activity was significantly inhibited by the transfection of short interfering RNA against MEK5 mRNA. An EGF receptor tyrosine kinase inhibitor, gefitinib ("Iressa", ZD1839), also significantly inhibited the abnormal growth of cultured BECs of PCK rats. By contrast, treatment with PD98059 and U0126, inhibitors for MEK1/2, was less effective. These results suggest that the activation of the MEK5-ERK5 cascade plays a pivotal role in the biliary dysgenesis of PCK rats, and also provide insights into the pathogenesis of Caroli's disease with CHF. As the MEK5-ERK5 interaction is highly specific, it may represent a potential target of therapy.