title: Gender-dependent hepatic alterations in H-ras12V transgenic mice.
abstract: OBJECTIVE
  Although it has been proposed that Ras and related signal pathways play important roles in hepatocarcinogenesis, appropriate in vivo models are lacking.
  
  
  METHODS
  Two hepatocellular carcinoma lines were established using pronuclear microinjection techniques to create an insertion of the H-ras12V transgene under the control of the albumin enhancer/promoter. The resulting phenotypes and related molecular events were then examined.
  
  
  RESULTS
  Male (but not female) transgenic mice older than 2 months showed hepatic alterations with a high degree of reproducibility, as compared to the wild-type mice. The liver/body-weight ratios were lower for the females than for the males. The transgene-carrying line 28 was investigated extensively with respect to molecular differences between the genders. Male hepatocytes showed higher Ras activity and higher reactive oxygen species (ROS) levels than female hepatocytes. The female hepatocytes showed higher expression levels of p53 and p21Waf1/Cip1, enhanced cytochrome c release, which correlated with cell cycle arrest, and higher levels of hypodiploid cell formation, as compared to the male hepatocytes.
  
  
  CONCLUSIONS
  The gender-related differences in molecular responses to activated Ras may have implications for the prevalence of hepatic alterations in males. Our transgenic mice represent a potentially valuable animal model for future investigations.
authors.affiliation: Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, South Korea.
authors.forename: Ai-Guo
authors.initials: AG
authors.lastname: Wang
authors.forename: Hyung-Bae
authors.initials: HB
authors.lastname: Moon
authors.forename: Mi-Ran
authors.initials: MR
authors.lastname: Lee
authors.forename: Chae Young
authors.initials: CY
authors.lastname: Hwang
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Kwon
authors.forename: Seong-Lan
authors.initials: SL
authors.lastname: Yu
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Kim
authors.forename: Mirang
authors.initials: M
authors.lastname: Kim
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Sang-Keun
authors.initials: SK
authors.lastname: Kim
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Lee
authors.forename: Eun-Yi
authors.initials: EY
authors.lastname: Moon
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Lee
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
mesh_terms: D000418:Albumins / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D011905:Genes, ras; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012737:Sex Factors; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000418:Albumins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins