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Regulation of p53 family member isoform DeltaNp63alpha by the nuclear factor-kappaB targeting kinase IkappaB kinase beta
- Source :
- Cancer research. 70(4)
- Publication Year :
- 2010
-
Abstract
- The p53 family (p53, p73, p63) plays an instrumental role in the cellular stress response, including induction of cell cycle arrest and apoptosis in response to DNA damage (1, 2). In addition to p63 and p73 isotypes capable of transactivating downstream target gene expression (TA isotypes), both genes also express dominant negative inhibitory isoforms, such as ΔNp63α. ΔNp63α is degraded in response to DNA damaging agents, thereby enabling an effective cellular response to genotoxic agents. Here, we identify a key molecular mechanism underlying the regulation of ΔNp63α expression in response to extrinsic stimuli, such as chemotherapeutic agents or TNF-α. We show that ΔNp63α interacts with IκB kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ (NEMO-NF-κB essential modifier). We find that IKKβ kinase promotes ubiquitin-mediated proteasomal degradation of ΔNp63α, whereas a kinase-deficient mutant IKKβ-K44A fails to do so. Cytokine- or chemotherapy-induced stimulation of IKKβ leads to degradation of ΔNp63α and augments trans-activation of p53 family-induced genes involved in the cellular response to DNA damage. Conversely, inhibition of IKKβ with a NEMO-binding peptide or siRNA-mediated silencing IKKβ expression attenuates cytokine- or chemotherapy induced degradation of ΔNp63α. These data demonstrate that IKKβ plays an essential role in regulating ΔNp63α in response to extrinsic stimuli. Our findings suggest that the activation of IKK may be a mechanism by which levels of ΔNp63α are reduced, thereby rendering the cells susceptible to cell death in the face of cellular stress or DNA damage.
- Subjects :
- Transcriptional Activation
Proteasome Endopeptidase Complex
Cell Death
Tumor Necrosis Factor-alpha
Ubiquitin
Tumor Suppressor Proteins
NF-kappa B
Article
I-kappa B Kinase
Enzyme Activation
Gene Expression Regulation, Neoplastic
Trans-Activators
Tumor Cells, Cultured
Humans
Protein Isoforms
Cisplatin
Tumor Suppressor Protein p53
Protein Processing, Post-Translational
DNA Damage
Protein Binding
Transcription Factors
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 70
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.pmid..........cd948efc4134a99f0f19eae13ba06401