title: IκB kinase β (IKKβ) inhibits p63 isoform γ (TAp63γ) transcriptional activity.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: Jun-Ming
authors.initials: JM
authors.lastname: Liao
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Liao
authors.forename: Sheyla X
authors.initials: SX
authors.lastname: Zeng
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Su
authors.forename: Elsa R
authors.initials: ER
authors.lastname: Flores
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
mesh_terms: D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation; D009539:Nicotinic Acids / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C501280:2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperidin-4-yl nicotinonitrile; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009539:Nicotinic Acids; D009570:Nitriles; D020033:Protein Isoforms; C115051:TP63 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D012694:Serine; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051550:I-kappa B Kinase
keywords: IκB kinase-β; Senescence; Signal transduction; Transcription; Tumor Necrosis Factor (TNF); p300; p63