Activated p53 induces NF-kappaB DNA binding but suppresses its transcriptional activation.
NF-kappaB plays an important role in oncogenesis. Recently, we have demonstrated that loss of p53 function enhances DNA binding and transcriptional activities of NF-kappaB via IKKalpha and IKKbeta, and that glycolysis, activated by NF-kappaB, 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-kappaB component, and enhances DNA-binding activity of NF-kappaB. However, activated p53 suppresses transcriptional activity of NF-kappaB. Under non-stimulating conditions, p65 formed a complex with IKKalpha and IKKbeta. Activated p53 bound to p65 on DNA and disrupted binding of p65 to IKKbeta. Moreover, histone H3 kinase activity, which requires transcriptional activation of NF-kappaB, was diminished by p53. Thus, activated p53 may suppress transcriptional activity of NF-kappaB through inhibition of IKK and histone H3 kinase on DNA, suggesting a novel p53-mediated suppression system for tumorigenesis.
Kawauchi
Keiko
K
Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, Kosugi-cho 1-396, Nakahara-ku, Kawasaki-shi, Kanagawa 211-8533, Japan.
Araki
Keigo
K
Tobiume
Kei
K
Tanaka
Nobuyuki
N
D000107:Acetylation; D000818:Animals; D004247:DNA / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D006656:Protamine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D012694:Serine / Q000378:metabolism; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D012694:Serine; D004247:DNA; D006656:Protamine Kinase; D051550:I-kappa B Kinase