J. Zalvide et Ja. Decaprio, ROLE OF PRB-RELATED PROTEINS IN SIMIAN-VIRUS-40 LARGE-T-ANTIGEN-MEDIATED TRANSFORMATION, Molecular and cellular biology, 15(10), 1995, pp. 5800-5810
Simian virus 40 large T-antigen (TAg) transformation is thought to be
mediated, at least in part, by binding to and modulating the function
of certain cellular proteins, including the retinoblastoma tumor suppr
essor gene product, pRb, TAg can disrupt the inhibitory complexes form
ed by pRb with the oncogenic transcription factor E2F, and this mechan
ism has been suggested to be important for TAg-mediated transformation
. Residues 102 to 114 of TAg (including the LXCXE motif) are required
for binding to pRb. Mutations within this LXCXE motif abolish the abil
ity of TAg to bind to pRb as well as to transform certain cell types.
TAg can also bind to at least two other cellular proteins, p107 and p1
30, that are related to pRb by sequence homology and share the ability
to bind E2F. However, whether p107 and p130 are also targets in TAg-m
ediated transformation is less clear. To assess the relative contribut
ion of the inactivation of pRb, p107, and p130 to transformation by TA
B, fibroblasts were prepared from embryos derived from matings of mice
heterozygous for an Rb knockout allele. The ability of TAg to transfo
rm fibroblasts homozygous for either wild-type or knockout Rb alleles
was evaluated. It is demonstrated that the integrity of the LXCXE moti
f provides a growth advantage in Rb+/+ and Rb-/- cells. Furthermore, w
ild-type TAg, but not the LXCXE mutants, could bind to p107 and p130 a
nd disrupt p107-E2F and p130-E2F binding complexes. These results sugg
est that p107 and p130 participate in TAg-mediated transformation and
that they may behave as tumor suppressors.