Role of NF-κB in p53-mediated programmed cell death

The tumour suppressor p53 inhibits cell growth through activation of cell-cycle arrest and apoptosis(1), and most cancers have either mutation within the p53 gene or defects in the ability to induce p53. Activation or re-introduction of p53 induces apoptosis in many tumour cells and may provide effective cancer therapy 2. One of the key proteins that modulates the apoptotic response is NF-kappa B, a transcription factor that can protect or contribute to apoptosis(3). Here we show that induction of p53 causes an activation of NF-kappa B that correlates with the ability of p53 to induce apoptosis. Inhibition or loss of NF-kappa B activity abrogated p53-induced apoptosis, indicating that NF-kappa B is essential in p53-mediated cell death. Activation of NF-kappa B by p53 was distinct from that mediated by tumour-necrosis factor-alpha and involved MEK1 and the activation of pp90(rsk). Inhibition of MEK1 blocked activation of NF-kappa B by p53 and completely abrogated p53-induced cell death. We conclude that inhibition of NF-kappa B in tumours that retain wild-type p53 may diminish, rather than augment, a therapeutic response.