Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis
- University of Michigan, United States
- Children's National Medical Center, United States
- University of Michigan Medical School and Comprehensive Cancer Center, United States
- Children's National Medical center, United States
Abstract
Cell-based studies showed that several Mdm2-binding ribosomal proteins, upon overexpression, stabilize and activate p53. In contrast, here we show in a mouse knockout study that Mdm2-binding ribosomal protein S27-like (Rps27l), upon disruption, activates p53. Germline inactivation of Rps27l triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53, leading to p53-dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which is rescued by Trp53 deletion. Paradoxically, while increased p53 is expected to inhibit tumorigenesis, Rps27l-/-;Trp53+/- mice develop lymphomas at higher incidence with p53 loss-of-heterozygosity and severe genome aneuploidy, suggesting that Rps27l disruption impose a selection pressure against p53. Thus, Rps27l has dual functions in p53 regulation: under Trp53+/+ background, Rps27l disruption triggers ribosomal stress to induce p53 and apoptosis, whereas under Trp53+/- background, Rps27l disruption triggers genomic instability and Trp53 deletion to promote tumorigenesis. Our study provides a new paradigm of p53 regulation.
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Ethics
Animal experimentation: All the animal procedures were approved by the University of Michigan Committee on Use and Care of Animals (Protocol # PRO00004764). Animal care was provided in accordance with the principles and procedures outlined in the National Research Council Guide for the Care and Use of Laboratory Animals.
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© 2014, Xiong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis
eLife 3:e02236.
https://doi.org/10.7554/eLife.02236
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