title: MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Guili
authors.initials: G
authors.lastname: Lian
authors.forename: Shuyong
authors.initials: S
authors.lastname: Lin
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Ye
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
mesh_terms: D017209:Apoptosis; D060466:Axin Protein / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D060466:Axin Protein; D002352:Carrier Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases