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

  1. Xiufang Xiong
  2. Yongchao Zhao
  3. Fei Tang
  4. Dongping Wei
  5. Daffyd Thomas
  6. Xiang Wang
  7. Yang Liu
  8. Pan Zheng
  9. Yi Sun  Is a corresponding author
  1. University of Michigan, United States
  2. Children's National Medical Center, United States
  3. University of Michigan Medical School and Comprehensive Cancer Center, United States
  4. 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.

Article and author information

Author details

  1. Xiufang Xiong

    University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yongchao Zhao

    University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Fei Tang

    Children's National Medical Center, Washington, DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dongping Wei

    University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Daffyd Thomas

    University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiang Wang

    University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yang Liu

    Children's National Medical Center, Washington, DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Pan Zheng

    Children's National Medical center, Washington, DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. 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.

Copyright

© 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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  1. Xiufang Xiong
  2. Yongchao Zhao
  3. Fei Tang
  4. Dongping Wei
  5. Daffyd Thomas
  6. Xiang Wang
  7. Yang Liu
  8. Pan Zheng
  9. Yi Sun
(2014)
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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https://doi.org/10.7554/eLife.02236

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