Hs. Symonds et al., USE OF TRANSGENIC MICE REVEALS CELL-SPECIFIC TRANSFORMATION BY A SIMIAN VIRUS-40 T-ANTIGEN AMINO-TERMINAL MUTANT, Molecular and cellular biology, 13(6), 1993, pp. 3255-3265
We have used the multifunctional transforming protein, simian virus 40
T antigen, as a probe to study the mechanisms of cell growth regulati
on in the intact organism. T antigen appears to perturb cell growth, a
t least in part, by stably interacting with specific cellular proteins
that function to maintain normal cell growth properties. Experiments
in cultured cells indicate that at least three distinct regions of sim
ian virus 40 T antigen have roles in transformation. Two regions corre
late with the binding of known cellular proteins, p53, pRB, and p107.
A third activity, located near the amino terminus, has been defined ge
netically but not biochemically. By targeting expression of wild-type
and mutant forms of T antigen to distinct cell types in transgenic mic
e, we have begun to systematically determine which activities play a r
ole in tumorigenesis of each cell type. In this study, we sought to de
termine the role of the amino-terminal transformation function with su
ch an analysis of the T-antigen mutant dl1135. This protein, which lac
ks amino acids 17 to 27, retains the p53-, pRB-, and p107-binding acti
vities yet fails to transform cells in culture. To direct expression i
n transgenic mice, we used the lymphotropic papovavirus transcriptiona
l signals that are specific for B and T lymphocytes and the choroid pl
exus epithelium of the brain. We show here that although defective in
cell culture, dl1135 specifically induced the development of thymic ly
mphomas in the mouse. Expression of the protein was routinely observed
in B- and T-lymphoid cells, although B-cell abnormalities were not ob
served. Choroid plexus tumors were observed only infrequently; however
, dl1135 was not consistently expressed in this tissue. Within a given
transgenic line, the penetrance of T-cell tumorigenesis was 100% but
appeared to require secondary events, as judged from the clonal nature
of the tumors. These experiments suggest that the amino-terminal regi
on of T antigen has a role in the transformation of certain cell types
(such as fibroblasts in culture and B lymphocytes) but is dispensable
for the transformation of T lymphocytes.