Wild-type p53 demonstrates functional dominance in a human colon carcinoma cell line in which it induces reversible growth arrest.

Abstract

We have introduced an inducible wild-type p53 allele into the human SW480 colon cancer cell line, which bears an endogenous mutant p53 allele. The expression of inducible wild-type p53 is under basal repression by the lac repressor and is induced by isopropyl-beta-thiogalactopyranoside. The addition of isopropyl-beta-thiogalactopyranoside induces expression of wild-type p53 transcript and protein at a level no greater than that of the endogenous mutant p53. This level of wild-type p53 induction is sufficient both to induce expression of WAF1/CIP1 and to induce G1 cell cycle arrest. This p53-induced growth arrest is reversible after 6 days of continuous p53 expression, indicating that apoptosis is not induced. These results demonstrate that in a human colon epithelial cell background, wild-type p53 is functionally dominant over this mutant p53 and thus provides a mechanism for the observed inactivation of both copies of the p53 gene in most colon cancers. Moreover, despite the well-documented role of apoptosis in maintaining homeostasis in the nontransformed colon epithelium, these results demonstrate that restoration of wild-type p53 expression is insufficient to trigger apoptosis of transformed colonic cells.