p53 induces NF-kappaB activation by an IkappaB kinase-independent mechanism involving phosphorylation of p65 by ribosomal S6 kinase 1.
Apoptosis induced by p53 has been proposed to involve activation of the transcription factor NF-kappaB. Here we describe the novel molecular mechanism through which p53 and DNA-damaging agents activate NF-kappaB. NF-kappaB induction by p53 does not occur through classical activation of the IkappaB kinases and degradation of IkappaBalpha. Rather, p53 expression stimulates the serine/threonine kinase ribosomal S6 kinase 1 (RSK1), which in turn phosphorylates the p65 subunit of NF-kappaB. The lower affinity of RSK1-phosphorylated p65 for its negative regulator, IkappaBalpha, decreases IkappaBalpha-mediated nuclear export of shuttling forms of NF-kappaB, thereby promoting the binding and action of NF-kappaB on cognate kappaB enhancers. These findings highlight a rather unusual pathway of NF-kappaB activation, which is utilized by the p53 tumor suppressor.
Bohuslav
Jan
J
Gladstone Institute of Virology and Immunology and the Department of Medicine, University of California, San Francisco, California 94143-1234, USA.
Chen
Lin-Feng
LF
Kwon
Hakju
H
Mu
Yajun
Y
Greene
Warner C
WC
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016328:NF-kappa B; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse