A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression Public Deposited

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Creator
  • Steinbrecher, Kris A.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, School of Medicine
  • Anest, Vasiliki
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, School of Medicine, Curriculum in Genetics and Molecular Biology
  • Strahl, Brian
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, School of Medicine, Department of Biochemistry and Biophysics, Curriculum in Genetics and Molecular Biology
  • Cogswell, Patricia C.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, School of Medicine
  • Hanson, Julie L.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, School of Medicine, Curriculum in Genetics and Molecular Biology
  • Baldwin, Albert
    • ORCID: https://orcid.org/0000-0003-1246-1346
    • Affiliation: College of Arts and Sciences, Department of Biology, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, School of Medicine
Abstract
  • NF-κB is a principal transcriptional regulator of diverse cytokine-mediated processes and is tightly controlled by the IκB kinase complex (IKK-α/β/γ). IKK-β and IKK-γ are critical for cytokine-induced NF-κB function, whereas IKK-α is thought to be involved in other regulatory pathways. However, recent data suggest a role for IKK-α in NF-κB-dependent gene expression in response to cytokine treatment. Here we demonstrate nuclear accumulation of IKK-α after cytokine exposure, suggesting a nuclear function for this protein. Consistent with this, chromatin immunoprecipitation (ChIP) assays reveal that IKK-α was recruited to the promoter regions of NF-κB-regulated genes on stimulation with tumour-necrosis factor-α. Notably, NF-κB-regulated gene expression is suppressed by the loss of IKK-α and this correlates with a complete loss of gene-specific phosphorylation of histone H3 on serine 10, a modification previously associated with positive gene expression. Furthermore, we show that IKK-α can directly phosphorylate histone H3 in vitro, suggesting a new substrate for this kinase. We propose that IKK-α is an essential regulator of NF-κB-dependent gene expression through control of promoter-associated histone phosphorylation after cytokine exposure. These findings provide additional insight into the role of the IKK complex in NF-κB-regulated gene expression.
Date of publication
Identifier
  • 2-s2.0-0037497184
  • doi:10.1038/nature01648
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • Nature
Journal volume
  • 423
Journal issue
  • 6940
Page start
  • 659
Page end
  • 663
Language
  • English
Version
  • Postprint
ISSN
  • 1476-4687
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