Mutant p53 exerts its gain of function through activation of the NF-κB pathway

Excerpt

The p53 gene is subject to frequent mutations in tumors, often leading to accumulation of excess mutant p53 protein, which can exhibit biological gain of function. In particular, mutant p53 exerts anti-apoptotic effects. Likewise, NF-κ B is a potent inhibitor of apoptosis, whose extended activation can promote cancer. We discovered that mutant p53 is in complex with the p65 NF-κ B subunit in tumor cells treated with TNF, a potent inducer of NF-κ B. In addition, we demonstrated that mutant p53 enhances the transcriptional activity of NF-κ B and its anti-apoptotic efficacy. Moreover, we were able to show that mutant p53 and NF-κ B are recruited together with the p300 acetyltransferase to anti-apoptotic target gene promoters. Interestingly, mutant p53 ablation attenuates the activity of NF-κ B and renders cancer cells susceptible to killing by TNF. Finally, we observed a close correlation between the high frequency of p53 mutations and the elevated expression of NF-κ B target genes in breast tumors. Therefore, our findings support an important role of NF-κ B in mediating the oncogenic activities of mutant p53 in tumor cells. …