The amino-terminal region of SV40 large T antigen is sufficient to induce hepatic tumours in mice.
The transforming activity of SV40 large T-antigen (Tag) depends on its binding to cellular proteins involved in the control of the cell cycle (p53, pRb, p300..) and on the J-domain region in the amino-terminus. We established transgenic lines expressing wild-type or Tag mutant proteins lacking one of the three transforming domains, to determine the respective contributions of these domains to hepatic tumour formation. Tag mutants with no pRb-binding domain or N-terminal fragment did not cause neoplastic liver abnormalities. The d11137 Tag mutant protein, which inhibits pRb function without affecting p53, induced hepatic tumours. These tumours grew significantly faster than those induced by wild-type Tag. Our results demonstrate different requirements for each of the inactivating functions of SV40 Tag in hepatocyte transformation and show that the loss of p53 function has only a moderate effect on hepatic tumour formation.
INSERM U-380, ICGM, Paris, France.
M
M
Bennoun
G
G
Grimber
D
D
Couton
A
A
Seye
T
T
Molina
P
P
Briand
V
V
Joulin
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics* / Q000378:metabolism; D000990:Antithrombin III / Q000235:genetics; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000990:Antithrombin III