Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis

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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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Xiufang Xiong

University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Yongchao Zhao

University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Fei Tang

Children's National Medical Center, Washington, DC, United States

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The authors declare that no competing interests exist.
Dongping Wei

University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Daffyd Thomas

University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, United States

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The authors declare that no competing interests exist.
Xiang Wang

University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Yang Liu

Children's National Medical Center, Washington, DC, United States

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The authors declare that no competing interests exist.
Pan Zheng

Children's National Medical center, Washington, DC, United States

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The authors declare that no competing interests exist.
Yi Sun

University of Michigan, Ann Arbor, United States

For correspondence
sunyi@umich.edu

Competing interests
The authors declare that no competing interests exist.

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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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.