Cul4A is an oncogene in malignant pleural mesothelioma.
Cul4A is an oncogene in malignant pleural mesothelioma.
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DOI：
10.1111/j.1582-4934.2009.00971.x
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发表时间：
2011-02
影响因子：
5.3
通讯作者：
You L
中科院分区：
文献类型：
--
作者：
Hung MS;Mao JH;Xu Z;Yang CT;Yu JS;Harvard C;Lin YC;Bravo DT;Jablons DM;You L
Cullin 4A（Cul 4A）在细胞存活、发育、生长和细胞周期中起重要作用，但其在间皮瘤中的作用尚未研究。对于第一次，我们确定了Cul 4A基因的扩增在四个间皮瘤细胞系。与Cul 4A基因拷贝数增加一致，我们发现Cul 4A蛋白在间皮瘤细胞中也过表达。Cul 4A蛋白在64%的原发性恶性胸膜间皮瘤（MPM）肿瘤中也过表达。此外，在间皮瘤细胞中用shRNA敲低Cul 4A导致在H290、H28和MS-1间皮瘤细胞系中p21和p27肿瘤抑制蛋白以不依赖于p53的方式上调。Cul 4A的敲除还导致H290、H28和MS-1间皮瘤细胞系中的G 0/G1细胞周期停滞和集落形成减少。此外，在Cul 4A敲低的H290细胞系中，G 0/G1细胞周期阻滞被siRNA下调p21和/或p27部分逆转。相反，Cul 4A的过表达导致H28间皮瘤细胞系中p21和p27蛋白的下调和集落形成的增加。p21和p27在Cul 4A过表达的H28细胞系中均表现出较快的降解速率，而在Cul 4A敲低的H28细胞系中表现出较慢的降解速率。我们的研究表明Cul 4A扩增和过表达在间皮瘤的发病机制中起致癌作用。因此，Cul 4A可能是MPM潜在的治疗靶点。
Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up-regulation of p21 and p27 tumour suppressor proteins in a p53-independent manner in H290, H28 and MS-1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS-1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down-regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down-regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for MPM.
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影响因子：
13.5
作者：
Yasui, K;Arii, S;Inazawa, J
通讯作者：
Inazawa, J
影响因子：
10.5
作者：
Osaka, F;Kawasaki, H;Kato, S
通讯作者：
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56.9
作者：
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通讯作者：
Roberts, JM
影响因子：
5.3
作者：
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通讯作者：
Raychaudhuri, P
影响因子：
64.8
作者：
Fero, ML;Randel, E;Kemp, CJ
通讯作者：
Kemp, CJ