Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration
Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration
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DOI：
10.1002/hep.20156
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发表时间：
2004-04-01
期刊：
影响因子：
13.5
通讯作者：
Michalopoulos, GK
中科院分区：
文献类型：
--
作者：
Köhler, C;Bell, AW;Michalopoulos, GK
Notch/Jagge信号通路在细胞分化和增殖中起重要作用。它的功能障碍与包括肝脏在内的几个组织的人类病理有关。Jagge-1基因点突变是Alagille综合征的原因，与肝内胆管缺乏有关。为探讨跨膜受体Notch及其配体Jagge-1在肝再生中的作用，我们观察了2/3肝部分切除后大鼠肝脏中Notch及其配体Jagge-1的表达。正常大鼠肝组织免疫组织化学染色显示，Notch表达于肝细胞、胆管细胞和内皮细胞，而Jagge-1表达于胆管细胞和肝细胞。Notch-1和Jagge-1蛋白均上调。肝部分切除后肝细胞中Notch胞浆结构域(NICD)的核易位增加，并在15min内达到高峰，表明Notch激活。Notch依赖靶基因(HES-1)的表达在30-60分钟内增加。在原代培养的肝细胞中加入重组Jagge-1蛋白可刺激肝细胞DNA合成。此外，在肝部分切除前2天向肝脏注射针对Notch和Jagge-1的沉默RNA显著抑制再生反应第2至4天的肝细胞增殖。总之，Notch/Jagge信号通路在肝脏再生过程中被激活，并可能参与影响细胞生长和分化的信号。本文的补充材料可在肝病网站(http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).上找到
The Notch/Jagged signaling pathway is important for cellular differentiation and proliferation. Its dysfunction is associated with human pathologies in several tissues including liver. Point mutations in Jagged-1 gene are the cause for Alagille syndrome, associated with paucity of intrahepatic bile ducts. To determine the putative role of the trans-membrane receptor Notch and its ligand Jagged-1 in liver regeneration, we investigated the expression of Notch and Jagged-1 in rat liver following 2/3 partial hepatectomy. Immunohistochemical staining of normal rat liver showed that Notch was expressed in hepatocytes, bile duct cells and endothelial cells, whereas Jagged-1 was expressed in bile duct cells and hepatocytes. Both Notch-1 and Jagged-1 proteins were upregulated. in hepatocytes after partial hepatectomy up to day 4. After partial hepatectomy, nuclear translocation of the intracellular cytoplasmic domain of Notch (NICD) increased and peaked within 15 minutes, indicating the activation of Notch. Expression of the Notch-dependent target gene (HES-1) expression increased within 30-60 minutes. Addition of recombinant Jagged-1 protein to primary cultures of hepatocytes stimulated hepatocyte DNA synthesis. Furthermore, injection of silencing RNA for Notch and Jagged-1 to livers 2 days before partial hepatectomy significantly suppressed proliferation of hepatocytes at days 2 to 4 of the regenerative response. In conclusion, Notch/Jagged signaling pathway is activated during liver regeneration and is potentially contributing to signals affecting cell growth and differentiation. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).