Ribosomal protein S7 as a novel modulator of p53–MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function

Abstract

As a major negative regulator of p53, the MDM2 oncogene plays an important role in carcinogenesis and tumor progression. MDM2 promotes p53 proteasomal degradation and negatively regulates p53 function. The mechanisms by which the MDM2-p53 interaction is regulated are not fully understood, although several MDM2-interacting molecules have recently been identified. To search for novel MDM2-binding partners, we screened a human prostate cDNA library by the yeast two-hybrid assay using full-length MDM2 protein as the bait. Among the candidate proteins, ribosomal protein S7 was identified and confirmed as a novel MDM2-interacting protein.Herein, we demonstrate that S7 binds to MDM2, in vitro and in vivo, and that the interaction between MDM2 and S7 leads to modulation of MDM2-p53 binding by forming a ternary complex among MDM2, p53 and S7. This results in the stabilization of p53 protein through abrogation of MDM2-mediated p53 ubiquitination. Consequently, S7 overexpression increases p53 transactivational activities, induces apoptosis, and inhibits cell proliferation. The identification of S7 as a novel MDM2-interacting partner contributes to elucidation of the complex regulation of the MDM2-p53 interaction and has implications in cancer prevention and therapy.

Ribosomopathies: human disorders of ribosome dysfunction

“…91 MDM2 has also been shown to bind specifically to several free ribosomal proteins, including RPL5, RPL23, RPL11, RPS7, and RPL26. [92][93][94][95][96][97][98] In an elegant series of experiments, nucleolar disruption, experimentally induced by treatment with actinomycin D, was shown to lead to the release of RPL11 and other ribosomal proteins into the nucleoplasm, the binding of RPL11 to MDM2, the inhibition of MDM2 activity, and the consequent accumulation of p53. 75,95 A schematic view of this pathway is shown in Figure 3A.…”

Updates on p53: modulation of p53 degradation as a therapeutic approach

“…It will, however, be critically important to further validate these targets using genetic and aptamer strategies in whole animals, and this could also rest upon their selective overexpression in particular tumour types. In addition, other identified cellular factors that modulate the p53 -Mdm2 interactions are gankyrin, L11, p14arf, p300, YYI and more recently, the ribosomal protein S7, which stabilises WT p53 by interacting with the p53 -Mdm2 complex and preventing the ubiquitination of p53 (Chen et al, 2007). Understanding and exploiting the mechanisms of action of these natural inducers of WT p53 stability offer promising avenues for therapy.…”

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

“…Following these initial reports, additional evidence subsequently was produced to support the roles of RPS7 (Chen et al, 2007;Zhu et al, 2009), RPL26 (Ofir-Rosenfeld et al, 2008 and RPS3 (Yadavilli et al, 2009) as Mdm2-binding partners. These studies served as the initial framework for establishing an RP-Mdm2-p53 stress response pathway.…”