Liver-specific expression of p53-negative regulator mdm2 leads to growth retardation and fragile liver in zebrafish.
Tumorigenesis requires inactivation of the p53 tumor suppressor pathway, likely involving the negative regulator Mdm2 protein. To analyze the possible roles of Mdm2 in oncogenesis and other functions during zebrafish hepatogenesis, we generated transgenic zebrafish by liver-specific Mdm2 over-expression utilizing a fusion between genes encoding GFP and mdm2, GFP::Mdm2. Over-expression of GFP::Mdm2 in the zebrafish liver did not interrupt normal liver development in the larval stages but approximately 30% of the adult fish raised from the same larvae displayed obvious growth retardation at 16 weeks of age. Most growth-retarded adults displayed liver atrophy, contraction, or hypoplasia, which proved lethal within 4 to 8 months. Histologically, over-expression of GFP::Mdm2 in Gmdm2-liver leading to liver degeneration may in some way have been due to an increased cell apoptosis accompanied by a slightly interrupted cell cycle or hepatocyte proliferation. Liver degeneration or other transgenic phenotypes were not associated with liver cancer; however, liver-degenerated phenotypes could be passed to wild-type zebrafish. In this study, we generated transgenic zebrafish lines with a "fragile liver." The "fragile liver" zebrafish can provide a model for molecular pathology of liver diseases and for screening small molecules that affect mdm2-related pathways.
Chen
Li-Je
LJ
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
Hsu
Chia-Chun
CC
Hong
Jiann-Ruey
JR
Jou
Luen-Kuang
LK
Tseng
Hung-Chia
HC
Wu
Jen-Leih
JL
Liou
Yih-Cherng
YC
Her
Guor Mour
GM
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002453:Cell Cycle / Q000502:physiology; D016923:Cell Death; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D008969:Molecular Sequence Data; D009024:Morphogenesis; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000033:anatomy & histology* / Q000378:metabolism / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D051736:Proto-Oncogene Proteins c-mdm2; C497209:mdm2 protein, zebrafish