p53-mediated induction of Noxa and p53AIP1 requires NFκB

The intricate regulation of cell survival and cell death is critical for the existence of both normal and transformed cells. Two factors central to these processes are p53 and NF kappa B, with both factors having ascribed roles in both promoting and repressing cell death. Not surprisingly, a number of studies have previously reported interplay between p53 and NF kappa B. The mechanistic basis behind these observations, however, is currently incomplete. We report here further insights into this interplay using a system where blockade of NF kappa B inhibits cell death from p53, but at the same time sensitizes cells to death by TNF alpha. We found in agreement with a recent report showing that NF kappa B is required for the efficient activation of the BH3-only protein Noxa by the p53 family member p73, that p53's ability to induce Noxa is also impeded by inhibition of NF kappa B. In contrast to the regulation by p73, however, blockade of NF kappa B downstream of p53 decreases Noxa protein levels without effects on Noxa mRNA. Our further analysis of the effects of NF kappa B inhibition on p53 target gene expression revealed that while most target genes analysed where unaffected by blockade of NF kappa B, the p53-mediated induction of the pro-apoptotic gene p53AIP1 was significantly dependent on NF kappa B. These studies therefore add further insight into the complex relationship of p53 and NF kappa B. In addition, since both Noxa and p53AIP1 have been shown to be important components of p53-mediated cell death responses, these findings may also indicate critical points where NF kappa B plays a pro-apoptotic role downstream of p53.