Nuclear iASPP determines cell fate by selectively inhibiting either p53 or NF-κB

p53 and NF-kappa Bp65 are essential transcription factors (TFs) in the cellular response to stress. Two signaling systems can often be entwined together and generally produce opposing biological outcomes in a cell context-dependent manner. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) has the potential to inhibit both p53 and NF-kappa Bp65, yet how such activities of iASPP are integrated with cancer remains unknown. Here, we utilized different cell models with diverse p53/NF-kappa Bp65 activities. An iASPP(295-828) mutant, which is exclusively located in the nucleus and has been shown to be essential for its inhibitory effects on p53/NF-kappa Bp65, was used to investigate the functional interaction between iASPP and the two TFs. The results showed that iASPP inhibits apoptosis under conditions when p53 is activated, while it can also elicit a proapoptotic effect when NF-kappa Bp65 alone is activated. Furthermore, we demonstrated that iASPP inhibited the transcriptional activity of p53/NF-kappa Bp65, but with a preference toward p53, thereby producing an antiapoptotic outcome when both TFs were simultaneously activated. This may be due to stronger binding between p53 and iASPP than NF-kappa Bp65 and iASPP. Overall, these findings provide important insights into how the activities of p53 and NF-kappa Bp65 are modulated by iASPP. Despite being a well-known oncogene, iASPP may have a proapoptotic role, which will guide the development of iASPP-targeted therapies to reach optimal outcomes in the future.

Automated summary

The study reveals that iASPP can inhibit apoptosis when p53 is activated, but may promote apoptosis when NF-kappa Bp65 is activated. iASPP preferentially inhibits the transcriptional activity of p53 over NF-kappa Bp65, resulting in an antiapoptotic outcome when both TFs are simultaneously activated.