The tumour suppressor p53 inhibits cell growth through activation of cell-c
ycle 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-intr
oduction of p53 induces apoptosis in many tumour cells and may provide effe
ctive cancer therapy 2. One of the key proteins that modulates the apoptoti
c response is NF-kappa B, a transcription factor that can protect or contri
bute to apoptosis(3). Here we show that induction of p53 causes an activati
on of NF-kappa B that correlates with the ability of p53 to induce apoptosi
s. Inhibition or loss of NF-kappa B activity abrogated p53-induced apoptosi
s, indicating that NF-kappa B is essential in p53-mediated cell death. Acti
vation of NF-kappa B by p53 was distinct from that mediated by tumour-necro
sis factor-alpha and involved MEK1 and the activation of pp90(rsk). Inhibit
ion of MEK1 blocked activation of NF-kappa B by p53 and completely abrogate
d p53-induced cell death. We conclude that inhibition of NF-kappa B in tumo
urs that retain wild-type p53 may diminish, rather than augment, a therapeu
tic response.