Regulation of p53 family member isoform ΔNp63α by the nuclear factor-κB targeting kinase IκB kinase β

Aditi Chatterjee, Xiaofei Chang, Tanusree Sen, Rajani Ravi, Atul Bedi, David Sidransky

Research output: Contribution to journalArticle

Abstract

The p53 family gene p63 plays an instrumental role in cellular stress responses including responses to DNA damage. In addition to encoding a full-length transcriptional activator, p63 also encodes several dominant inhibitory isoforms including the isoform ΔNp63α, the function of which is not fully understood. ΔNp63α is degraded in response to DNA damage, thereby enabling an effective cellular response to genotoxic agents. Here, we identify a key molecular mechanism underlying regulation of ΔNp63α expression in response to chemotherapeutic agents or tumor necrosis factor-α. We found that ΔNp63α interacts with IκB kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKKκ and IKKβ, and a regulatory subunit, IKKγ. The IKKβ kinase promotes ubiquitin-mediated proteasomal degradation of ΔNp63α, whereas a kinasedeficient mutant IKKβ-K44A fails to do so. Cytokine- or chemotherapy-induced stimulation of IKKβ caused degradation of ΔNp63α and augmented transactivation of p53 family-induced genes involved in the cellular response to DNA damage. Conversely, IKKβ inhibition attenuated cytokine- or chemotherapy-induced degradation of ΔNp63α. Our findings show that IKKβ plays an essential role in regulating ΔNp63α in response to extrinsic stimuli. IKK activation represents one mechanism by which levels of ΔNp63α can be reduced, thereby rendering cells susceptible to cell death in the face of cellular stress or DNA damage.

Original languageEnglish (US)
Pages (from-to)1419-1429
Number of pages11
JournalCancer Research
Volume70
Issue number4
DOIs
StatePublished - Feb 15 2010

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DNA Damage
Protein Isoforms
Phosphotransferases
Cytokines
Drug Therapy
p53 Genes
Ubiquitin
Protein Kinases
Transcriptional Activation
Catalytic Domain
Cell Death
Tumor Necrosis Factor-alpha
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Regulation of p53 family member isoform ΔNp63α by the nuclear factor-κB targeting kinase IκB kinase β. / Chatterjee, Aditi; Chang, Xiaofei; Sen, Tanusree; Ravi, Rajani; Bedi, Atul; Sidransky, David.

In: Cancer Research, Vol. 70, No. 4, 15.02.2010, p. 1419-1429.

Research output: Contribution to journalArticle

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