Abstract
We have previously shown that after DNA-damage, the p52 NF-kB subunit can function cooperatively with the p53 tumor suppressor to both repress and induce Skp2 expression. However, the wider role and activation of p52 after DNA-damage has not been determined. Activation of NF-kB in response to DNA break inducers can be mediated by ATM (ataxia telangiectasia mutated)-dependent phosphorylation of NEMO (NF-kB essential modulator), resulting in IKKβ mediated induction of the classical NF-kB pathway, leading to the induction of RelA(p65)/p50 dimers. Here, we show that DNA damage also induces p100 (NF-kB2) processing to generate active p52. We further demonstrate that p52 generation is dependent not only on IKKα but also on atypical activation by NEMO/ATM. Moreover, we identify a post-DNA damage, positive feedback loop of p52 activation through induction of NF-kB2 gene expression, involving both the classical and alternative NF-kB pathways. Gene expression and chromatin immunoprecipitation analyses indicated DNA damage induced p52 dimer recruitment on multiple, p53 dependent and independent, target genes associated with promoting cell cycle arrest and cell death. These results demonstrate an important role for the alternative, p52 NF-kB pathway after DNA-damage distinct from its functions as a regulator of adaptive immunity.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Adaptive Immunity / physiology
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Antineoplastic Agents / metabolism
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Apoptosis / genetics
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cisplatin / metabolism
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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DNA Damage*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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NF-kappa B p52 Subunit / genetics
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NF-kappa B p52 Subunit / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction / physiology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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CCND1 protein, human
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Cell Cycle Proteins
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DNA-Binding Proteins
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I-kappa B Proteins
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IKBKG protein, human
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MYC protein, human
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NF-kappa B p52 Subunit
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Cyclin D1
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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I-kappa B Kinase
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Cisplatin