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- Title
Lung tumourigenesis in a conditional Cul4A transgenic mouse model.
- Authors
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
- Abstract
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 tumour development . After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry ( IHC) revealed decreased levels of Cul4A-associated proteins p21CIP1 and tumour suppressor p19ARF in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27KIP1 and p16INK4a were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed 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 over-expression 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. Published by John Wiley & Sons, Ltd
- Publication
Journal of Pathology, 2014, Vol 233, Issue 2, p113
- ISSN
0022-3417
- Publication type
Article
- DOI
10.1002/path.4352