IκB Kinase β Promotes Cell Survival by Antagonizing p53 Functions through ΔNp73α Phosphorylation and Stabilization

Delta Np73 alpha, a dominant-negative inhibitor of p53 and p73, exhibits antiapoptotic and transforming activity in in vitro models and is often found to be upregulated in human cancers. The mechanisms involved in the regulation of Delta Np73 alpha protein levels in normal and cancer cells are poorly characterized. Here, we show that that I kappa B kinase beta (IKK beta) increases Delta Np73 alpha protein stability independently of its ability to activate NF-kappa B. IKK beta associates with and phosphorylates Delta Np73 alpha at serine 422 (S422), leading to its accumulation in the nucleus, where it binds and represses several p53-regulated genes. S422A mutation in Delta Np73 alpha abolished IKK beta-mediated stabilization and inhibition of p53-regulated gene expression. Inhibition of IKK beta activity by chemical inhibitors, overexpression of dominant-negative mutants, or gene silencing by siRNA also resulted in Delta Np73 alpha destabilization, which under these conditions was rapidly translocated into the cytoplasm and degraded by a calpain-mediated mechanism. We also present evidence for the IKK beta and Delta Np73 alpha cross talk in cancer-derived cell lines and primary cancers. Our data unveil a new mechanism involved in the regulation of the p73 and p53 network.