WILD-TYPE-P53 DIFFERENTIALLY AFFECTS TUMORIGENIC AND METASTATIC POTENTIAL OF MURINE METASTATIC CELL VARIANTS

The structure and the function of the p53 gene were studied in two met astatic cell variants derived from Lewis lung carcinoma. Single missen se mutation at codon 334 was detected in the p53 gene of both cell var iants. In spite of the identical mutation, the in vitro and in vivo gr owth rates of the two cell variants were differentially affected by th e constitutive expression of exogenous wild-type (wt) p53 gene. In fac t, only the more malignant cell line (C87) was severely affected by th e wt-p53 gene introduction. However, the in vivo effects on this cell line were transient because during serial in vivo passages, cell popul ations lacking the wt-p53 gene were selected. Genetic mechanisms respo nsible for the resistance of the less metastatic cell variant (BC215) to the wt-p53 expression, were investigated. Intrinsic ability to muta te exogenous cDNA sequences was tested. We report that BC215 cells con tinued to express exogenous wt-p53 sequences after several in vitro pa ssages. The expression of mdm2 gene was evaluated. The data demonstrat ed that BC215 cells constitutively express higher levels of mdm2 gene than C87 cells. We conclude that the overexpression of this gene might be responsible for the resistance of BC215 cells to exogenous wt-p53 gene expression.