NF-kappa B plays an important role in oncogenesis. Recently, we have demonstrated that loss of p53 function enhances DNA binding and transcriptional activities of NF-kappa B via IKK alpha and IKK beta, and that glycolysis, activated by NF-kappa B, has an integral role in oncogene-induced cell transformation. Here, we show that ectopically expressed p53 induces acetylation and phosphorylation at Ser 536 of p65, an NF-kappa B component, and enhances DNA-binding activity of NF-kappa B. However, activated p53 suppresses transcriptional activity of NF-kappa B. Under non-stimulating conditions, p65 formed a complex with IKK alpha and IKK beta. Activated p53 bound to p65 on DNA and disrupted binding of p65 to IKK beta. Moreover, histone H3 kinase activity, which requires transcriptional activation of NF-kappa B, was diminished by p53. Thus, activated p53 may suppress transcriptional activity of NF-kappa B through inhibition of IKK and histone H3 kinase on DNA, suggesting a novel p53-mediated suppression system for tumorigenesis. (C) 2008 Elsevier Inc. All rights reserved.