The amino-terminal region of SV40 large T antigen is sufficient to induce hepatic tumours in mice

Abstract

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 Jdomain 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 dl1137 Tag mutant protein, which inhibits pRb function without aecting p53, induced hepatic tumours. These tumours grew signi®cantly faster than those induced by wild-type Tag. Our results demonstrate dierent 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 eect on hepatic tumour formation.

Transforming functions of Simian Virus 40

“…On the other hand, T antigen-induced carcinogenesis of pancreatic beta cells is reduced when the expression of p53 is abolished in this tissue, perhaps in response to the lower levels of T antigen found in cells lacking p53 compared to wild-type tumor cells (Herzig et al, 1999). Finally, the loss of p53 function caused by interaction with T antigen only has only a moderate e ect on hepatic tumor formation, while it remains completely dependent on the disruption of the Rb pathway (Bennoun et al, 1998). Similarly, the presence or absence of p53 do not seem to a ect the T antigen-induced transformation of the intestinal epithelium (Coopersmith et al, 1997;Kim et al, 1993).…”

“…Some tissue types require a functional T antigen/p53 binding domain for oncogenic transformation (McCarthy et al, 1994;Sa enz-Robles et al, 1994), while in other cases the binding of T antigen to p53 is not required for induction of tumors (Bennoun et al, 1998;Chen et al, 1992;Tevethia et al, 1997b). In the case of choroid plexus epithelium, the J domain coupled with the Rb-binding motif induces hyperplasia as e ciently as full length T antigen.…”

“…In most cases tested, the amino terminal region of LT (comprising the J domain and Rb binding motif) is necessary and su cient to induce tumors in various murine tissues, in a manner that absolutely requires an intact Rb-interaction domain (Bennoun et al, 1998;Chandrasekaran et al, 1996;Chen et al, 1992;Kim et al, 1994;Sa enz Robles et al, 1994). The role of the J domain has been less studied in transgenic models, and the reports so far indicate an important -although tissue-speci®c-dependency on the J domain to induce tumors (Chen et al, 1992;Ratineau et al, 2000;Symonds et al, 1993).…”

The consequence of p53 overexpression for liver tumor development and the response of transformed murine hepatocytes to genotoxic agents

“…It has previously been shown that this promoter/enhancer gives transgene expression in liver (Bennoun et al, 1998;Dubois et al, 1991) and kidney (Tremp et al, 1995). Three independent AT3-p53 lines were established (designated lines A, B and C).…”

“…We next tested the eect of p53 in another model of hepatocarcinoma induced by TAg deleted in its p53-binding domain (TAgDp53 also called dl1137) (Bennoun et al, 1998). TAgDp53 mice expressed a cytoplasmic TAg mutant that does not stabilize endogenous p53.…”