ATM kinase is a master switch for the ΔNp63α phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon DNA damage

Yiping Huang, Tanusree Sen, Jatin Nagpal, Sunil Upadhyay, Barry Trink, Edward Ratovitski, David Sidransky

Research output: Contribution to journalArticlepeer-review

Abstract

We previously found that the pro-apoptotic DNA damaging agent, cisplatin, mediated the proteasome-dependent degradation of ΔNp63α associated with its increased phosphorylated status. Since ΔNp63α usually plays an opposite role to p53 and TAp63 in human cancers, we tested the notion that phosphorylation events induced by DNA damage would affect the protein degradation of ΔNp63α in HNSCC cells upon cisplatin exposure. We found that ΔNp63α is phosphorylated in the time-dependent fashion at the following positions: S385, T397 and S466, which were surrounded by recognition motifs for ATM, CDK2 and p70s6K kinases, respectively. We showed that chemical agents or siRNA inhibiting the activity of ATM, CDK2 and p70s6K kinases blocked degradation of ΔNp63α in HNSCC cells after cisplatin exposure. Site-specific mutagenesis of ΔNp63α residues targeted for phosphorylation by ATM, CDK2 or p70s6k led to dramatic modulation of ΔNp63α degradation. Finally, we demonstrated that the ΔNp63α protein is a target for direct in vitro phosphorylation by ATM, CDK2 or p70s6K. Our results implicate specific kinases, and target phosphorylation sites in the degradation of ΔNp63α following DNA damage.

Original languageEnglish (US)
Pages (from-to)2846-2855
Number of pages10
JournalCell Cycle
Volume7
Issue number18
DOIs
StatePublished - Sep 15 2008

Keywords

  • Cisplatin
  • DNA damage
  • Kinases
  • Phosphorylation
  • Squamous
  • Stress
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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