Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding

The critical tumor suppressor p53 is mutated or functionally inactivated in nearly all cancers. We have shown previously that the MDM2-MDMX complex functions as an integral unit in targeting p53 for degradation. Here we identify the small protein 14-3-3 as a binding partner of MDMX, which binds at t...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-05, Vol.283 (20), p.13707-13713
Main Authors: Lopez-Pajares, Vanessa, Kim, Mihee M., Yuan, Zhi-Min
Format: Article
Language:English
Subjects:
14-3-3 Proteins - metabolism
Amino Acid Motifs
Amino Acid Sequence
Cell Cycle Proteins
Cell Line
Gene Expression Regulation
Humans
Models, Biological
Molecular Sequence Data
Nuclear Proteins - metabolism
Nuclear Proteins - physiology
Phosphorylation
Protein Binding
Protein Structure, Tertiary
Protein Synthesis, Post-Translational Modification, and Degradation
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins - physiology
Proto-Oncogene Proteins c-akt - metabolism
Sequence Homology, Amino Acid
Tumor Suppressor Protein p53 - chemistry
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Summary:The critical tumor suppressor p53 is mutated or functionally inactivated in nearly all cancers. We have shown previously that the MDM2-MDMX complex functions as an integral unit in targeting p53 for degradation. Here we identify the small protein 14-3-3 as a binding partner of MDMX, which binds at the C terminus (Ser367) in a phosphorylation-dependent manner. Importantly, we demonstrate that the serine/threonine kinase Akt mediates phosphorylation of MDMX at Ser367. This phosphorylation leads to stabilization of MDMX and consequent stabilization of MDM2. Previous studies have shown that Akt phosphorylates and stabilizes MDM2. Our data suggest that stabilization of MDMX by Akt may be an alternative mechanism by which Akt up-regulates MDM2 protein levels and exerts its oncogenic effects on p53 in tumor cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M710030200