Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Cell Line
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Cell Nucleus / metabolism
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Cytoplasm / metabolism
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DNA Damage
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Enzyme Activation
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Fibroblasts / metabolism
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Gene Silencing
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Genes, Reporter
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Humans
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I-kappa B Kinase
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Mice
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Models, Biological
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Mutation
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NF-kappa B / metabolism*
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Phosphorylation
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Precipitin Tests
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Small Interfering / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Transcription Factor RelA
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Transcription, Genetic
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Transfection
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Tumor Suppressor Protein p53 / metabolism*
Substances
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NF-kappa B
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RNA, Small Interfering
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Transcription Factor RelA
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Tumor Suppressor Protein p53
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Protein Serine-Threonine Kinases
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RPS6KA1 protein, human
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Ribosomal Protein S6 Kinases, 90-kDa
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Rps6ka1 protein, mouse
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse