Tumor necrosis factor reduces c-myc expression and cooperates with interferon-gamma in HeLa cells.

The suppression of the c-myc nuclear oncogene is associated with growth arrest and may therefore be directly controlled by naturally occurring growth inhibitors. The effect of tumor necrosis factor (TNF) and of interferon-gamma (IFN-gamma) on c-myc expression was investigated in HeLa cells, which respond to these cytokines by a specific arrest in the G0/G1 phase of the cell cycle. Northern blot and nuclear transcription analyses indicated that each cytokine reduced within 1 to 3 hours the c-myc messenger RNA levels as a result of transcriptional inhibition. Adding the two cytokines together at saturating levels resulted in enhanced inhibition of c-myc transcription and of the c-myc messenger RNA steady-state levels. While the reduction of c-myc messenger RNA by IFN-gamma was dependent on new protein synthesis, the inhibitory effect of TNF on c-myc messenger RNA was direct and was not abrogated by cycloheximide. The differential effect of the protein synthesis inhibitor and the cooperative inhibitory effects of the two cytokines when added together suggest that IFN-gamma and TNF reduce c-myc transcription through different molecular mechanisms.