Abstract
p53 and NF-κBp65 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-κBp65, yet how such activities of iASPP are integrated with cancer remains unknown. Here, we utilized different cell models with diverse p53/NF-κBp65 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-κBp65, 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-κBp65 alone is activated. Furthermore, we demonstrated that iASPP inhibited the transcriptional activity of p53/NF-κBp65, 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-κBp65 and iASPP. Overall, these findings provide important insights into how the activities of p53 and NF-κBp65 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.
Highlights
Mammalian cells are unavoidably and continually affronted by various stresses
RESULTS Inhibitor of apoptosis-stimulating protein of p53 (iASPP)(295–828) acts as an apoptotic inhibitor by blocking the transcriptional activity of p53 To understand the biological outcomes of nuclear iASPP activity in regulating p53 and NF-κBp65, we first examined the functional interaction between iASPP and p53 under conditions when p53 was activated but NF-κBp65 was inactivated
P53 was activated (indicated by increased p53 levels and PIG3 (p53 inducible protein 3) luciferase activity) after treatment of p53wild type MCF-7 cells with the MDM2 inhibitor Nutlin-3; treatment had no obvious effect on the expression levels of NFκBp65 or NF-κBp65 activation, as indicated by p-NF-κBp65 (Fig. 1A)
Summary
Mammalian cells are unavoidably and continually affronted by various stresses. To maintain tissue homeostasis, a diverse range of mechanisms have been developed. IASPP(295–828) has the ability to promote apoptosis by inhibiting the transcriptional activity of NF-κBp65 iASPP was first identified as being able to bind to and inhibit an NF-κBp65 subunit; the biological significance of this interaction in the context of apoptotic regulation is not yet known.
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