title: Accelerated hepatocellular carcinoma development in CUL4B transgenic mice.
abstract: Cullin 4B (CUL4B) is a component of the Cullin 4B-Ring E3 ligase (CRL4B) complex that functions in proteolysis and in epigenetic regulation. CUL4B possesses tumor-promoting properties and is markedly upregulated in many types of human cancers. To determine the role of CUL4B in liver tumorigenesis, we generated transgenic mice that expressed human CUL4B in livers and other tissues and evaluated the development of spontaneous and chemically-induced hepatocellular carcinomas. We observed that CUL4B transgenic mice spontaneously developed liver tumors at a high incidence at old ages and exhibited enhanced DEN-induced hepatocarcinogenesis. There was a high proliferation rate in the livers of CUL4B transgenic mice that was accompanied by increased levels of Cdk1, Cdk4 and cyclin D1 and decreased level of p16. The transgenic mice also exhibited increased compensatory proliferation after DEN-induced liver injury, which was accompanied by activation of Akt, Erk, p38 and NF-κB. We also found that Prdx3 was downregulated and that DEN induced a higher level of reactive oxygen species in the livers of transgenic mice. Together, our results demonstrate a critical role of CUL4B in hepatocarcinogenesis in mice.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Jupeng
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Life Science, Jinan, China.
authors.forename: Aizhen
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Haining
authors.initials: H
authors.lastname: Tan
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Life Science, Jinan, China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Gao
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D044842:Cullin Proteins / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004789:Enzyme Activation; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D061105:Peroxiredoxin III / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; C524851:Cul4B protein, mouse; D044842:Cullin Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016328:NF-kappa B; C516116:Prdx3 protein, mouse; D017382:Reactive Oxygen Species; D019938:Cyclin D1; D061105:Peroxiredoxin III; D016203:CDC2 Protein Kinase; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D020928:Mitogen-Activated Protein Kinases
keywords: CUL4B transgenic mice; DEN; HCC; ROS; proliferation