Sh. Kim et al., EXPRESSION OF WILD-TYPE AND MUTANT SIMIAN-VIRUS-40 LARGE TUMOR-ANTIGENS IN VILLUS-ASSOCIATED ENTEROCYTES OF TRANSGENIC MICE, Proceedings of the National Academy of Sciences of the United Statesof America, 91(15), 1994, pp. 6914-6918
The four principal gut epithelial cell lineages undergo continuous and
rapid renewal during a geographically well-organized migration along
the crypt-to-villus axis. The molecules that regulate their proliferat
ion and differentiation programs are largely unknown. The large tumor
antigen (TAg) of wild-type (wt) simian virus 40 (SV40) and its mutant
derivatives represent tools for describing the contributions of regula
tors of the cell cycle to the proliferative state of each lineage. Exp
ression of SV40 TAgwt in postmitotic, villus-associated enterocytes of
transgenic mice causes them to reenter the cell cycle without an appa
rent effect on their state of differentiation. When human ERAS with a
Val-12 substitution ([Val(12)]KRAS) is coexpressed with SV40 TAgwt in
villus enterocytes of bitransgenic animals, the two oncoproteins coope
rate to produce dedifferentiation (dysplasia). SV40 mutant dl1137 expr
esses a TAg that is unable to complex with p53 but retains N-terminal
transforming functions, including the ability to complex pRB, p107, an
d p300. When SV40 TAgdl1137 is expressed in villus enterocytes, they r
eenter into the cell cycle. However, coexpression of SV40 TAgdl1137 an
d [Val(12)]KRAS does not produce dysplastic changes. Thus, the N-termi
nal 121 residues of TAg are sufficient to perturb the proliferative st
ate of the enterocyte but not to produce detectable changes in the sta
te of differentiation when coexpressed with [Val(12)]KRAS.