Article
- The EMBO Journal (2006) 25, 1196 - 1206
- doi:10.1038/sj.emboj.7601032
Published online: 2 March 2006
Subject Category:
Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
Cynthia LeBron, Lihong Chen, Daniele M Gilkes and Jiandong Chen
- Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
Correspondence to:
Jiandong Chen, Molecular Oncology Program, H Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Drive, Tampa, FL 33612, USA. Tel.: +1 813 903 6822; Fax: +1 813 903 6817; E-mail: jchen@moffitt.usf.edu
Received 18 October 2005; Accepted 13 February 2006
Abstract
The MDM2 homolog MDMX is an important regulator of p53 during mouse embryonic development. DNA damage promotes MDMX phosphorylation, nuclear translocation, and degradation by MDM2. Here we show that MDMX copurifies with 14-3-3, and DNA damage stimulates MDMX binding to 14-3-3. Chk2-mediated phosphorylation of MDMX on S367 is important for stimulating 14-3-3 binding, MDMX nuclear import by a cryptic nuclear import signal, and degradation by MDM2. Mutation of MDMX S367 inhibits ubiquitination and degradation by MDM2, and prevents MDMX nuclear import. Expression of 14-3-3 stimulates the degradation of phosphorylated MDMX. Chk2 and 14-3-3 cooperatively stimulate MDMX ubiquitination and overcome the inhibition of p53 by MDMX. These results suggest that MDMX–14-3-3 interaction plays a role in p53 response to DNA damage by regulating MDMX localization and stability.
Keywords:
- Chk2,
- MDM2,
- MDMX,
- p53,
- 14-3-3
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