title: Lung tumourigenesis in a conditional Cul4A transgenic mouse model.
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 p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) 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.
authors.affiliation: Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Yang
authors.forename: Ming-Szu
authors.initials: MS
authors.lastname: Hung
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Ni
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: David
authors.initials: D
authors.lastname: Hsieh
authors.forename: Alfred
authors.initials: A
authors.lastname: Au
authors.forename: Atul
authors.initials: A
authors.lastname: Kumar
authors.forename: David
authors.initials: D
authors.lastname: Quigley
authors.forename: Li Tai
authors.initials: LT
authors.lastname: Fang
authors.forename: Che-Chung
authors.initials: CC
authors.lastname: Yeh
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
authors.forename: Liang
authors.initials: L
authors.lastname: You
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C114234:CUL4A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; C493975:Cdkn2d protein, mouse; D018797:Cell Cycle Proteins; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; C498645:Ris2 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002945:Cisplatin
keywords: Ad-Cre; Cul4A; cell cycle; non-small cell lung cancer; transgenic mouse models