Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-kappa B activation

Abstract

Normal fibroblasts are resistant to the cytotoxic action of tumor necrosis 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 signaling responses in fibroblasts containing a conditionally active c‐Myc protein. In association with cell death, c‐Myc impaired TNF‐induced activation of phospholipase A2, JNK protein kinase and cell survival‐signaling‐associated NF‐κB transcription factor complex. The TNF‐induced death of mouse primary fibroblasts expressing deregulated c‐Myc was inhibited by transient overexpression of the p65 subunit of NF‐κB, which increased NF‐κB activity in the cells. Unlike other TNF‐induced signals, TNF‐induced accumulation of the wild‐type p53 mRNA and protein was not inhibited by c‐Myc. TNF, with c‐Myc, induced apoptosis in mouse primary fibroblasts but only weakly in p53 ‐deficient primary fibroblasts. The C‐terminal domain of p53, which is a transacting dominant inhibitor of wild‐type p53, failed to inhibit apoptosis by c–Myc and TNF, suggesting that the cell death was not dependent on the transcription‐activating function of p53. Taken together, the present findings show that the cytotoxic activity of TNF towards oncoprotein‐expressing cells involves p53 and an impaired signaling for survival in such cells.