Down-regulation of nuclear factor kappa B is required for p53-dependent apoptosis in X-ray-irradiated mouse lymphoma cells and thymocytes

Transcription factors p53 and nuclear factor kappa B (NF-kappa B) have been implicated in apoptosis induced by DNA-damaging agents, but the relationsh ip between these two factors at the molecular level is largely unknown, We have isolated apoptosis-resistant mutant sublines from a radiosensitive mou se lymphoma 3SB cell line that undergoes p53-dependent apoptosis after X-ra y irradiation, and we have analyzed the NF-kappa B activity, Two of these a poptosis-resistant sublines expressed mutant p53 protein and exhibited a de fect in the induction of cyclin-dependent kinase inhibitor p21 after X-ray irradiation, A decrease in the DNA binding activity of NF-kappa B was obser ved in the parental 3SB cells after exposure to X-rays, whereas the same ac tivity was unaffected by radiation in the two mutant sublines. A similar do wn-regulation of NF-kappa B activity by X-rays was observed in thymocytes d erived from p53 wild-type and heterozygous mice, but not in thymocytes from p53 homozygous knockout mice. These results suggest that NF-kappa B inacti vation is p53 dependent and is required for X-ray-induced apoptosis in thym ic lymphoma cells and normal thymocytes.