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PMID: 22777350 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Identification of ribosomal protein S25 (RPS25)-MDM2-p53 regulatory feedback loop.

Oncogene ·Vol. 32 ·No. 22 ·2013-05-30 ·Pages 2782-91

Zhang X, Wang W, Wang H, Wang MH, Xu W, Zhang R

Abstract

There is an increasing interest in determining the role of ribosomal proteins (RPs) in the regulation of MDM2-p53 pathway in coordinating cellular response to stress. Herein, we report a novel regulatory role of ribosomal protein S25 (RPS25) in MDM2-mediated p53 degradation and a feedback regulation of S25 by p53. We demonstrated that S25 interacted with MDM2 and inhibited its E3 ligase activity, resulting in the reduction of MDM2-mediated p53 ubiquitination and the stabilization and activation of p53. S25, MDM2 and p53 formed a ternary complex following ribosomal stress. The nucleolar localization and MDM2-binding domains of S25 were critical for its role in MDM2-mediated p53 regulation. Knockdown of S25 by siRNA attenuated the induction and activation of p53 following ribosomal stress. S25 stabilized and cooperated with MDMX to regulate MDM2 E3 ligase activity. Furthermore, S25 was identified to be a transcriptional target of p53; p53 directly bound to S25 promoter and suppressed S25 expression. Our results suggest that there is a S25-MDM2-p53 regulatory feedback loop, which may have an important role in cancer development and progression.

MeSH Terms
Animals COS Cells Cell Cycle/genetics Cell Cycle Proteins Cell Line, Tumor Cell Nucleolus/metabolism Chlorocebus aethiops Feedback, Physiological Humans Nuclear Proteins/metabolism Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-mdm2/metabolism RNA Interference RNA, Small Interfering Ribosomal Proteins/genetics,metabolism Transcription, Genetic Tumor Suppressor Protein p53/metabolism Ubiquitin-Protein Ligases/metabolism Ubiquitination
Chemicals
Cell Cycle Proteins MDM4 protein, human Nuclear Proteins Proto-Oncogene Proteins RNA, Small Interfering RPS25 protein, human Ribosomal Proteins TP53 protein, human Tumor Suppressor Protein p53 MDM2 protein, human Proto-Oncogene Proteins c-mdm2 Ubiquitin-Protein Ligases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Zhang X
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, TX 79106, USA.
Wang W
Wang H
Wang M-H
Xu W
Zhang R
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2012.289
Published
2013-05-30
Epub
2012-00-09
Pages
2782-91
Language
English
Region
England
NLM ID
8711562
PMCID
PMC6714567
Subset
IM
Grants
NCI NIH HHS · R01 CA091980 · United States
NCI NIH HHS · R01 CA112029 · United States
NCI NIH HHS · R01 CA121211 · United States
NCI NIH HHS · R01 CA91980 · United States
External Links
PubMed source DOI: 10.1038/onc.2012.289 PMC Full Text View journal details
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