The p53 homologue ΔNp63α interacts with the nuclear factor-κB pathway to modulate epithelial cell growth

The p53 homologue Delta Np63 alpha is overexpressed and inhibits apoptosis in a subset of human squamous cell carcinomas (SCC). Here, we report that in normal keratinocytes over-expressing Delta Np63 alpha and in human squamous carcinoma cells, Delta Np63 alpha physically associates with phosphorylated, transcriptionally active nuclear c-Rel, a nuclear factor-kappa B family member, resulting in increased c-Rel nuclear accumulation. This accumulation and the associated enhanced proliferation driven by elevated Delta Np63 alpha are attenuated by c-Rel small interfering RNA or overexpression of mutant I kappa B alpha M, indicating that c-Rel-containing complex formation is critical to the ability of elevated Delta Np63 alpha to maintain proliferation in the presence of growth arresting signals. Consistent with a role in growth regulation, Delta Np63 alpha-c-Rel complexes bind a promoter motif and repress the cyclin-dependent kinase inhibitor p21WAF1 in both human squamous carcinoma cells and normal keratinocytes overexpressing Delta Np63 alpha. The relationship between Delta Np63 alpha and activated c-Rel is reflected in their strong nuclear staining in the proliferating compartment of primary head and neck SCC. This is the first report indicating that high levels of Delta Np63 alpha interact with activated c-Rel in keratinocytes and SCC, thereby promoting uncontrolled proliferation, a key alteration in the pathogenesis of cancers.