EXPRESSION OF WILD-TYPE AND MUTANT SIMIAN-VIRUS-40 LARGE TUMOR-ANTIGENS IN VILLUS-ASSOCIATED ENTEROCYTES OF TRANSGENIC MICE

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.