STRESS-INDUCED SECRETION OF GROWTH-INHIBITORS - A NOVEL TUMOR-SUPPRESSOR FUNCTION OF P53

p53 tumor suppressor gene controls cell response to a variety of stres ses inducing growth arrest or apoptosis in damaged cells. It largely d etermines the sensitivity of tumor and normal cells to radiation and c hemotherapy, and, therefore, defines both the efficacy and limitations of anti-cancer treatment. To determine molecular mechanisms of p53-de pendent stress response in normal tissues we identified and compared t he spectra of radiation-responsive genes in cells of different origin and p53 status using a cDNA array hybridization technique. The majorit y of genes identified were p53-dependent and cell type specific, Sever al of the new p53 responders encode known secreted growth inhibitory f actors, This suggests that p53, in addition to its intrinsic antiproli feration activity, can cause 'bystander effect' by inducing export of growth suppressive stimuli from damaged cells to neighboring cells. Co nsistently, a p53-dependent accumulation of factors, which causes grow th inhibitory effects in a variety of cell lines, was found after gamm a irradiation in the media from established and primary cell cultures and in the urine of irradiated mice. Moreover, p53-dependent factors r eleased by normal human fibroblasts potentiated the cytotoxic effect o f a chemotherapeutic drug on co-cultivated tumor cells. This suggests a previously unknown role for normal cells in chemo- and radiation the rapy of cancer.