Department of Molecular Genetics, The Rappaport Family Institute for Research in the Medical Sciences, Haifa, Israel.
Mol Cancer. 2010 Mar 9;9:54. doi: 10.1186/1476-4598-9-54.
The AP-1 transcription factor plays a major role in cell proliferation, apoptosis, differentiation and developmental processes. AP-1 proteins are primarily considered to be oncogenic. Gene disruption studies placed c-Jun as an oncogene at the early stage of a mouse model of hepatocellular carcinoma. Mice lacking c-Jun display reduced number and size of hepatic tumors attributed to elevated p53 expression and increased apoptosis. This suggests that c-Jun inhibition may serve as a therapeutic target for liver cancer. The c-Jun dimerization protein 2, JDP2 is an AP-1 repressor protein that potently inhibits AP-1 transcription. On the other hand, the JDP2 locus was found at a recurring viral integration site in T-cell lymphoma. We sought to examine the potential of JDP2 to inhibit c-Jun/AP-1 oncogenic activity in mice. Towards this end, we generated a tetracycline inducible transgenic mouse expressing JDP2 specifically in the liver. We used diethylnitrosamine (DEN) injection to initiate liver cancer in mice and assessed the extent of liver cancer in JDP2-transgenic and wild type control mice by biochemical and molecular biology techniques.
JDP2-transgenic mice display normal liver function. JDP2-transgenic mice displayed potentiation of liver cancer, higher mortality and increased number and size of tumors. The expression of JDP2 at the promotion stage was found to be the most critical for enhancing liver cancer severity.
This study suggests that JDP2 expression may play a critical role in liver cancer development by potentiating the compensatory proliferative response and increased inflammation in the DEN liver cancer model.
AP-1 转录因子在细胞增殖、凋亡、分化和发育过程中起着重要作用。AP-1 蛋白主要被认为是致癌的。基因敲除研究将 c-Jun 作为一种癌基因置于肝癌小鼠模型的早期阶段。缺乏 c-Jun 的小鼠表现出肝肿瘤数量和大小减少，这归因于 p53 表达升高和细胞凋亡增加。这表明 c-Jun 抑制可能成为肝癌的治疗靶点。c-Jun 二聚化蛋白 2（JDP2）是一种 AP-1 抑制蛋白，可强力抑制 AP-1 转录。另一方面，JDP2 基因座位于 T 细胞淋巴瘤中经常发生病毒整合的部位。我们试图研究 JDP2 抑制 c-Jun/AP-1 致癌活性的潜力。为此，我们构建了一种在肝脏中特异性表达 JDP2 的四环素诱导型转基因小鼠。我们使用二乙基亚硝胺（DEN）注射启动小鼠肝癌，并通过生化和分子生物学技术评估 JDP2 转基因和野生型对照小鼠的肝癌程度。
JDP2 转基因小鼠显示出正常的肝功能。JDP2 转基因小鼠显示出肝癌增强、死亡率增加以及肿瘤数量和大小增加。在促进阶段 JDP2 的表达被发现对增强肝癌严重程度最为关键。
这项研究表明，JDP2 表达可能通过增强 DEN 肝癌模型中的代偿性增殖反应和增加炎症在肝癌发生发展中起关键作用。
