IκB kinase β (IKKβ) inhibits p63 isoform γ (TAp63γ) transcriptional activity

J Biol Chem. 2013 Jun 21;288(25):18184-93. doi: 10.1074/jbc.M113.466540. Epub 2013 Apr 15.


Previously, we reported that IκB kinase-β(IKKβ) phosphorylates and stabilizes TAp63γ. However, the effect of this phosphorylation on TAp63γ transcriptional activity remains unclear. In this study, we showed that overexpression of IKKβ, but not its kinase dead mutant and IKKα, can surprisingly inhibit TAp63γ transcriptional activity as measured by luciferase assays and real-time PCR analyses of p63 target genes. This inhibition was impaired by ACHP, an IKKβ inhibitor, and enhanced by TNFα that activates IKKβ. Consistently, IKKβ inhibited the binding between TAp63γ and p300, a co-activator of TAp63γ, and consequently counteracted the positive effect of p300 on TAp63γ transcriptional activity. Through phosphorylation site prediction and mass spectrometry, we identified that Ser-4 and Ser-12 of p63 are IKKβ-targeting residues. As expected, IKKβ fails to suppress the transcriptional activity of the S4A/S12A double mutant p63. These results indicate that IKKβ can suppress TAp63γ activity by interfering with the interaction between TAp63γ and p300.

Keywords: IκB kinase-β; Senescence; Signal transduction; Transcription; Tumor Necrosis Factor (TNF); p300; p63.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / genetics
  • Blotting, Western
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism*
  • Gene Expression
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • MicroRNAs / genetics
  • Mutation
  • Nicotinic Acids / pharmacology
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine / genetics
  • Serine / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation*
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperidin-4-yl nicotinonitrile
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • MIRN34 microRNA, human
  • MicroRNAs
  • Nicotinic Acids
  • Nitriles
  • Protein Isoforms
  • TP63 protein, human
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Serine
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • I-kappa B Kinase