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ATM and Chk2‐dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
Author(s) -
Chen Lihong,
Gilkes Daniele M,
Pan Yu,
Lane William S,
Chen Jiandong
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600812
Subject(s) - biology , dna damage , phosphorylation , mdmx , dna , checkpoint kinase 2 , microbiology and biotechnology , genetics , cancer research , mdm2 , apoptosis , protein serine threonine kinases , protein kinase a
The p53 tumor suppressor is activated after DNA damage to maintain genomic stability and prevent transformation. Rapid activation of p53 by ionizing radiation is dependent on signaling by the ATM kinase. MDM2 and MDMX are important p53 regulators and logical targets for stress signals. We found that DNA damage induces ATM‐dependent phosphorylation and degradation of MDMX. Phosphorylated MDMX is selectively bound and degraded by MDM2 preceding p53 accumulation and activation. Reduction of MDMX level by RNAi enhances p53 response to DNA damage. Loss of ATM prevents MDMX degradation and p53 stabilization after DNA damage. Phosphorylation of MDMX on S342, S367, and S403 were detected by mass spectrometric analysis, with the first two sites confirmed by phosphopeptide‐specific antibodies. Mutation of MDMX on S342, S367, and S403 each confers partial resistance to MDM2‐mediated ubiquitination and degradation. Phosphorylation of S342 and S367 in vivo require the Chk2 kinase. Chk2 also stimulates MDMX ubiquitination and degradation by MDM2. Therefore, the E3 ligase activity of MDM2 is redirected to MDMX after DNA damage and contributes to p53 activation.