IκB kinase β promotes cell survival by Antagonizing p53 functions through ΔNp73α phosphorylation and stabilization

Rosita Accardi, Mariafrancesca Scalise, Tarik Gheit, Ishraq Hussain, Jiping Yue, Christine Carreira, Agnese Collino, Cesare Indiveri, Lutz Gissmann, Bakary S. Sylla, Massimo Tommasino

Research output: Contribution to journalArticle

Abstract

ΔNp73α, a dominant-negative inhibitor of p53 and p73, exhibits antiapoptotic and transforming activity in in vitro models and is often found to be upregulated in human cancers. The mechanisms involved in the regulation of ΔNp73α protein levels in normal and cancer cells are poorly characterized. Here, we show that that IκB kinase beta (IKKβ) increases ΔNp73α protein stability independently of its ability to activate NF-κB. IKKβ associates with and phosphorylates ΔNp73α at serine 422 (S422), leading to its accumulation in the nucleus, where it binds and represses several p53-regulated genes. S422A mutation in ΔNp73α abolished IKKβ-mediated stabilization and inhibition of p53-regulated gene expression. Inhibition of IKKβ activity by chemical inhibitors, overexpression of dominant-negative mutants, or gene silencing by siRNA also resulted in ΔNp73α destabilization, which under these conditions was rapidly translocated into the cytoplasm and degraded by a calpain-mediated mechanism. We also present evidence for the IKKβ and ΔNp73α cross talk in cancer-derived cell lines and primary cancers. Our data unveil a new mechanism involved in the regulation of the p73 and p53 network.

Original languageEnglish
Pages (from-to)2210-2226
Number of pages17
JournalMolecular and Cellular Biology
Volume31
Issue number11
DOIs
Publication statusPublished - Jun 2011

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Cell Survival
Phosphotransferases
Phosphorylation
p53 Genes
Neoplasms
I-kappa B Kinase
Calpain
Protein Stability
Gene Silencing
Serine
Small Interfering RNA
Cytoplasm
Gene Expression
Cell Line
Mutation
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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IκB kinase β promotes cell survival by Antagonizing p53 functions through ΔNp73α phosphorylation and stabilization. / Accardi, Rosita; Scalise, Mariafrancesca; Gheit, Tarik; Hussain, Ishraq; Yue, Jiping; Carreira, Christine; Collino, Agnese; Indiveri, Cesare; Gissmann, Lutz; Sylla, Bakary S.; Tommasino, Massimo.

In: Molecular and Cellular Biology, Vol. 31, No. 11, 06.2011, p. 2210-2226.

Research output: Contribution to journalArticle

Accardi, R, Scalise, M, Gheit, T, Hussain, I, Yue, J, Carreira, C, Collino, A, Indiveri, C, Gissmann, L, Sylla, BS & Tommasino, M 2011, 'IκB kinase β promotes cell survival by Antagonizing p53 functions through ΔNp73α phosphorylation and stabilization', Molecular and Cellular Biology, vol. 31, no. 11, pp. 2210-2226. https://doi.org/10.1128/MCB.00964-10
Accardi, Rosita ; Scalise, Mariafrancesca ; Gheit, Tarik ; Hussain, Ishraq ; Yue, Jiping ; Carreira, Christine ; Collino, Agnese ; Indiveri, Cesare ; Gissmann, Lutz ; Sylla, Bakary S. ; Tommasino, Massimo. / IκB kinase β promotes cell survival by Antagonizing p53 functions through ΔNp73α phosphorylation and stabilization. In: Molecular and Cellular Biology. 2011 ; Vol. 31, No. 11. pp. 2210-2226.
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