Lung tumourigenesis in a conditional Cul4A transgenic mouse model.
Lung tumourigenesis in a conditional Cul4A transgenic mouse model.
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条件性 Cul4A 转基因小鼠模型中的肺肿瘤发生
DOI：
10.1002/path.4352
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发表时间：
2014-06
影响因子：
7.3
通讯作者：
You, Liang
中科院分区：
文献类型：
--
作者：
Yang, Yi-Lin;Hung, Ming-Szu;Wang, Yang;Ni, Jian;Mao, Jian-Hua;Hsieh, David;Au, Alfred;Kumar, Atul;Quigley, David;Fang, Li Tai;Yeh, Che-Chung;Xu, Zhidong;Jablons, David M.;You, Liang
Cullin 4A（Cul 4A）是一种支架蛋白，其组装Cullin-RING泛素连接酶（E3）复合物并调节许多细胞事件，包括细胞存活、发育、生长和细胞周期控制。我们以前的研究表明Cul 4A在体外是致癌的，但其在体内的致癌作用还没有研究。在这里，我们使用Cul 4A转基因小鼠模型来研究Cul 4A在肺肿瘤发展中的潜在致癌作用。在肺中诱导Cul 4A过表达32周后，观察到非典型上皮细胞。40周后，可见肺肿瘤，并被表征为I级或II级腺癌。免疫组化（IHC）显示Cul 4A相关蛋白p21 CIP 1和肿瘤抑制因子p19 ARF在肺肿瘤中的水平降低，表明Cul 4A调节它们在这些肿瘤中的表达。在这些肿瘤中也检测到p27 KIP 1和p16 INK 4a水平升高。DNA复制许可因子CDT 1蛋白水平降低。通过比较基因组杂交分析和pericentrin蛋白表达结果进一步分析肺肿瘤中基因组的不稳定性。此外，在肺癌H2170细胞中敲低Cul 4A表达增加了它们对化疗药物顺铂的体外敏感性，表明Cul 4A过表达与癌细胞中的顺铂耐药性相关。我们的研究结果表明Cul 4A在体内是致癌的，这种Cul 4A小鼠模型是了解Cul 4A在人类癌症中的机制和测试靶向Cul 4A的实验疗法的工具。
Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth, and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumor development. After Cul4A overexpression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumors were visible and were characterized as Grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A associated proteins p21CIP1 and tumor suppressor p19ARF in the lung tumors, suggesting Cul4A regulated their expression in these tumors. Increased levels of p27KIP1 and p16INK4a were also detected in these tumors. Moreover, protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumors was further analyzed by the results from pericentrin protein expression and array Comparative Genomic Hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A overexpression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1083/jcb.200908114
发表时间：
2010-01-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Delaval B;Doxsey SJ
通讯作者：
Doxsey SJ
影响因子：
11.2
作者：
Kotake Y;Zeng Y;Xiong Y
通讯作者：
Xiong Y
影响因子：
5.3
作者：
Belani, CP;Langer, C
通讯作者：
Langer, C
影响因子：
16
作者：
Liu, Liren;Lee, Sharrell;Zhang, Jianxuan;Peters, Sara B.;Hannah, Jeffrey;Zhang, Yue;Yin, Yan;Koff, Andrew;Ima, Liang;Zhou, Pengbo
通讯作者：
Zhou, Pengbo