INDUCTION OF TNF-SENSITIVE CELLULAR PHENOTYPE BY C-MYC INVOLVES P53 AND IMPAIRED NF-KAPPA-B ACTIVATION

Normal fibroblasts are resistant to the cytotoxic action of tumor necr osis factor (TNF), but are rendered TNF-sensitive upon deregulation of c-Myc. To assess if oncoproteins induce the cytotoxic TNF activity by modulating TNF signaling, we investigated the TNF-elicited signalling responses in fibroblasts containing a conditionally active c-Myc prot ein. In association with cell death, c-Myc impaired TNF-induced activa tion of phospholipase A(2), JNK protein kinase and cell survival-signa ling-associated NF-kappa B activity in the cells. Unlike other TNF-ind uced signal, TNF-induced accumulation of the wild-type p53 mRNA and pr otein was not inhibited by c-Myc. TNF, with c-Myc, induced apoptosis i n mouse primary fibroblasts but only weakly in p53-deficient primary f ibroblasts. The C-terminal domain of p53, which is a transacting domin ant inhibitor of wild-type p53, failed to inhibit apoptosis by c-Myc a nd TNF, suggesting that the cell death was not dependent on the transc ription-activating function of p53. Taken together, the present findin gs show that the cytotoxic activity of TNF towards oncoprotein-express ing cells involves p53 and an impaired signaling for survival in such cells.