DNA damage-induced activation of ATM promotes β-TRCPmediated Mdm2 ubiquitination and destruction

Zhiwei Wang, Hiroyuki Inuzuka, Jiateng Zhong, Hidefumi Fukushima, Lixin Wan, Pengda Liu, Wenyi Wei

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

The Mdm2 oncoprotein promotes p53 ubiquitination and destruction. Yet, exact molecular mechanisms of Mdm2 destruction itself, under DNA damaging conditions, remain unclear. Recently, we identified SCFβ-TRCP as a novel E3 ligase that targets Mdm2 for ubiquitination and destruction in a Casein Kinase Id (CKId)-dependent manner. However, it remains elusive how the β-TRCP/CKId/Mdm2 signaling axis is regulated by DNA damage signals to govern p53 activity. Consistent with previous studies, we found that inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase, in turn, impaired DNA damage-induced Mdm2 destruction. Although phosphorylation of Mdm2 at Ser395 (an ATM phosphorylation site) facilitated Mdm2 interaction with β-TRCP, Ser395A-Mdm2 was degraded non-distinguishably from WT-Mdm2 by SCFβ-TRCP upon DNA damaging treatments. This indicates that in addition to phosphorylating Mdm2 at Ser395, ATM may govern Mdm2 stability through other unknown mechanisms. We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKId at two well-conserved S/TQ sites, which promotes CKId nuclear localization to increase CKId-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCFβ-TRCP. Our studies provide a molecular mechanism of how ATM could govern DNA damage-induced destruction of Mdm2 in part by phosphorylating both Mdm2 and CKId to modulate SCFβ-TRCP-mediated Mdm2 ubiquitination. Given the pivotal role of Mdm2 in the negative regulation of p53, this work will also provide a rationale for developing CKId or ATM agonists as anti-cancer agents.

Original languageEnglish
Pages (from-to)1026-1035
Number of pages10
JournalOncotarget
Volume3
Issue number9
DOIs
Publication statusPublished - 2012 Sep

Keywords

  • ATM
  • And cancer
  • CKId
  • DNA damage
  • Destruction
  • Mdm2
  • Ubiquitination
  • β-TRCP

ASJC Scopus subject areas

  • Oncology

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