MDMX exerts its oncogenic activity via suppression of retinoblastoma protein.
Inactivation of the retinoblastoma protein (RB) has a major role in the development of human malignancies. We have previously shown that MDM2, an ubiquitin E3 ligase and major negative regulator of p53, binds to and promotes proteasome-mediated degradation of RB. MDMX, a homolog of MDM2, also binds to and inhibits ... p53 transactivation activity, yet it does not possess intrinsic ubiquitin ligase activity. Here, we show that MDMX binds to and promotes RB degradation in an MDM2-dependent manner. Specifically, the MDMX C-terminal ring domain binds to the RB C-pocket and enhances MDM2-RB interaction. Silencing MDMX induces RB accumulation, cell cycle arrest and senescence-like phenotypes, which are reverted by simultaneous RB knockdown. Furthermore, MDMX ablation leads to significant retardation of xenograft tumor growth, concomitant with RB accumulation. These results demonstrate that MDMX exerts oncogenic activity via suppression of RB, and suggest that both MDM2 and MDMX could be chemotherapeutic targets.
Mesh Terms:
Animals, Carcinogenesis, Cell Cycle Checkpoints, Cell Line, Tumor, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Nuclear Proteins, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Retinoblastoma Protein, Tumor Suppressor Protein p53, Ubiquitin, Ubiquitin-Protein Ligases
Animals, Carcinogenesis, Cell Cycle Checkpoints, Cell Line, Tumor, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Nuclear Proteins, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Retinoblastoma Protein, Tumor Suppressor Protein p53, Ubiquitin, Ubiquitin-Protein Ligases
Oncogene
Date: Oct. 29, 2015
PubMed ID: 25703327
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