DNA damage-induced activation of ATM promotes ?-TRCP-mediated Mdm2 ubiquitination and destruction.

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 SCF?-TRCP as a novel E3 ligase that targets Mdm2 for ubiquitination and destruction in a Casein Kinase I? (CKI?)-dependent manner. However, it remains elusive how the ?-TRCP/CKI?/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 ?-TRCP, Ser395A-Mdm2 was degraded non-distinguishably from WT-Mdm2 by SCF?-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 CKI? at two well-conserved S/TQ sites, which promotes CKI? nuclear localization to increase CKI?-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCF?-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 CKI? to modulate SCF?-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 CKI? or ATM agonists as anti-cancer agents.

SUBMITTER: Wang Z 

PROVIDER: S-EPMC3660052 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature