The consequence of p53 overexpression for liver tumor development and the response of transformed murine hepatocytes to genotoxic agents.
To analyse the effect of p53 on liver tumor development, we generated transgenic mice overexpressing wild-type p53 in the liver and crossed them with transgenic mice in which the expression of the SV40 large T antigen (TAg) induces hepatic tumors. Remarkably, whereas preneoplastic TAg liver exhibited anisocaryosis and anisocytosis, TAg/p53 liver never presented any dysplastic cells. Moreover, whereas expression of p53 did not affect hepatic development, its constitutive expression in tumorigenic livers resulted in a significantly enhanced apoptosis once nodules had appeared. In contrast, p53 overexpression did not modify the elevated proliferation of TAg-transformed hepatocytes and had no effect on hepatocarcinoma progression. In vitro analysis of primary hepatocytes exposed to various genotoxic agents showed that p53 failed to sensitize normal or TAg-transformed hepatocytes to apoptosis, except when high doses of doxorubicin, UV-B and UV-C radiation were used. Our results confirmed that the hepatocyte cell type is very resistant to genotoxic agents and showed that constitutive expression of p53 failed to improve their responsiveness. In addition, our results showed that suppression of dysplastic cells, probably by restoring normal cytokinesis and karyokinesis, and enhancement of apoptosis by means of p53 overexpression were insufficient to counteract or delay the TAg-induced liver tumoral progression. Oncogene (2000) 19, 3498 - 3507
INSERM U380, Institut Cochin de Génétique Moléculaire, 22 rue Méchain, 75014 Paris, France.
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R
Gillet
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G
Grimber
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M
Bennoun
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Caron de Fromentel
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P
Briand
V
V
Joulin
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D001665:Binding Sites; D001835:Body Weight; D002461:Cell Line, Transformed / Q000187:drug effects / Q000528:radiation effects; D003433:Crosses, Genetic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics*; D018450:Disease Progression; D004317:Doxorubicin / Q000633:toxicity*; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005838:Genotype; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D008727:Methotrexate / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D009929:Organ Size; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D013539:Simian virus 40 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051028:bcl-2-Associated X Protein
D000952:Antigens, Polyomavirus Transforming; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D004247:DNA; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D008727:Methotrexate