title: Abnormal MDMX degradation in tumor cells due to ARF deficiency.
abstract: MDMX is a heterodimeric partner of MDM2 and a critical regulator of p53. The MDMX level is generally elevated in tumors with wild-type p53 and contributes to p53 inactivation. MDMX degradation is controlled in part by MDM2-mediated ubiquitination. Here, we show that MDMX turnover is highly responsive to changes in MDM2 level in non-transformed cells, but not in tumor cells. We found that loss of alternate reading frame (ARF) expression, which occurs in most tumors with wild-type p53, significantly reduces MDMX sensitivity to MDM2. Restoration of ARF expression in tumor cells enables MDM2 to degrade MDMX in a dose-dependent manner. ARF binds to MDM2 and stimulates a second-site interaction between the central region of MDM2 and MDMX, and thus increases MDMX-MDM2 binding and MDMX ubiquitination. These results reveal an important abnormality in the p53-regulatory pathway as a consequence of ARF deficiency. Loss of ARF during tumor development not only prevents p53 stabilization by proliferative stress but also causes accumulation of MDMX that compromises p53 activity. This phenomenon may reduce the clinical efficacy of MDM2-specific inhibitors by preventing MDMX downregulation.
authors: Molecular Oncology Department, Moffitt Cancer Center, Tampa, FL, USA.
authors: X
authors: X
authors: Li
authors: D
authors: D
authors: Gilkes
authors: B
authors: B
authors: Li
authors: Q
authors: Q
authors: Cheng
authors: D
authors: D
authors: Pernazza
authors: H
authors: H
authors: Lawrence
authors: N
authors: N
authors: Lawrence
authors: J
authors: J
authors: Chen
mesh_terms: D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D007093:Imidazoles; D007211:Indoles; C482775:MDM4 protein, human; C543589:MI-63 compound; D009687:Nuclear Proteins; D010879:Piperazines; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D013141:Spiro Compounds; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C482203:nutlin 1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex