Abstract
MDM2 plays a crucial role in negatively regulating the functions of tumor suppressor p53. Here we show that MDM2 can inhibit Axin-stimulated p53-dependent apoptosis by suppressing p53 phosphorylation at Ser 46 and apoptosis-related p53 transactivational activity. Interestingly, the ubiquitin E3 ligase activity of MDM2 is not required for this inhibitory effect. Mechanically, either wildtype MDM2 or its E3-dead mutant, disrupts the Axin-based HIPK2/p53 complex formation by blocking the binding of p53 and HIPK2 to Axin. MDM2Δp53, a deletion mutant that lacks p53 binding domain fails to exert the inhibitory effect, demonstrating that the interaction of MDM2 and p53, but not its E3 ligase activity toward p53 plays key role in suppressing Axin-stimulated p53 activation. Our results thus have revealed a novel aspect of the mechanism by which MDM2 regulates p53 activities.
MeSH terms
-
Apoptosis
-
Axin Protein / metabolism*
-
Carrier Proteins / metabolism*
-
Cell Proliferation
-
Cells, Cultured
-
HEK293 Cells
-
Humans
-
Mutation / genetics
-
Protein Serine-Threonine Kinases / metabolism*
-
Proto-Oncogene Proteins c-mdm2 / genetics
-
Proto-Oncogene Proteins c-mdm2 / metabolism*
-
Tumor Suppressor Protein p53 / metabolism*
-
Ubiquitin-Protein Ligases / metabolism*
Substances
-
Axin Protein
-
Carrier Proteins
-
TP53 protein, human
-
Tumor Suppressor Protein p53
-
MDM2 protein, human
-
Proto-Oncogene Proteins c-mdm2
-
Ubiquitin-Protein Ligases
-
HIPK2 protein, human
-
Protein Serine-Threonine Kinases
Grants and funding
This work was supported by the “973” program (2009CB522200), the grants from Natural Science Foundation of China (#31101014 and #30871280), the program for NCET-09-0675, the Fundamental Research Funds for the Central Universities (#2011) and the “project 111” (# B06016). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.