MAMMALIAN-CELLS RESISTANT TO TUMOR-SUPPRESSOR GENES

Expression of p53 causes growth arrest or apoptosis in many normal and neoplastic cell types, but the relationship between these two effects has remained obscure. To begin to dissect the underlying mechanisms a t a genetic level, we have generated mutant cells resistant to the act ion of wild-type p53, Rat embryo fibroblasts transformed with ras and a temperature-sensitive p53 (tsp53(135val)) gene were chemically mutag enized and selected for growth at a temperature at which p53 adopts a wild-type conformation (31.5 degrees C), Clones that grew exponentiall y at 31.5 degrees C were selected. Cell fusion experiments demonstrate d that the mutations conferring resistance to p53-mediated growth arre st were dominant. The mutagenized clones were resistant not only to p5 3-mediated growth arrest, but also to the apoptosis induced by E1A in conjunction with p53, and partially resistant to the retino-blastoma t umor suppressor, pRB. The results suggest that a single downstream pat hway san control the induction of growth arrest and apoptosis, and tha t both p53 and RB function through this pathway.