Induction of TNF-sensitive Cellular Phenotype by c-Myc Involves p53 and Impaired NF-kappaB Activation

EMBO J. 1997 Dec 15;16(24):7382-92. doi: 10.1093/emboj/16.24.7382.


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-kappaB 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-kappaB, which increased NF-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Embryo, Mammalian
  • Enzyme Activation
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Insulin-Like Growth Factor I / pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Membrane Proteins / metabolism
  • Mice
  • Mitogen-Activated Protein Kinases*
  • NF-kappa B / metabolism*
  • Phospholipases A / metabolism
  • Phospholipases A2
  • Proto-Oncogene Proteins c-myc / biosynthesis*
  • Proto-Oncogene Proteins c-myc / physiology
  • RNA, Messenger / biosynthesis
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Suppressor Protein p53 / biosynthesis*
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / physiology
  • bcl-2 Homologous Antagonist-Killer Protein


  • Bak1 protein, mouse
  • Bak1 protein, rat
  • Membrane Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • bcl-2 Homologous Antagonist-Killer Protein
  • Insulin-Like Growth Factor I
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Phospholipases A
  • Phospholipases A2