SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer

  1. Ziling Fang
  2. Bo Cao
  3. Jun-Ming Liao
  4. Jun Deng
  5. Kevin D Plummer
  6. Peng Liao
  7. Tao Liu
  8. Wensheng Zhang
  9. Kun Zhang
  10. Li Li
  11. David Margolin
  12. Shelya X Zeng  Is a corresponding author
  13. Jianping Xiong  Is a corresponding author
  14. Hua Lu  Is a corresponding author
  1. Tulane University School of Medicine, United States
  2. Southern New Hampshire University, United States
  3. Xavier University of Louisiana, United States
  4. Ochsner Clinical Foundation, United States
  5. The First Affiliated Hospital of Nanchang University, China

Abstract

Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity towards p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.

Article and author information

Author details

  1. Ziling Fang

    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Bo Cao

    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jun-Ming Liao

    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jun Deng

    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kevin D Plummer

    Department of Economy, Southern New Hampshire University, New Hampshire, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Peng Liao

    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Tao Liu

    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Wensheng Zhang

    Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Kun Zhang

    Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Li Li

    Laboratory Translational Cancer Research, Ochsner Clinical Foundation, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. David Margolin

    Department of Colon and Rectal Surgery, Ochsner Clinical Foundation, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Shelya X Zeng

    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
    For correspondence
    szeng@tulane.edu
    Competing interests
    The authors declare that no competing interests exist.
  13. Jianping Xiong

    Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
    For correspondence
    jpxiong@ncu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  14. Hua Lu

    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
    For correspondence
    hlu2@tulane.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9285-7209

Funding

National Cancer Institute

  • Hua Lu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Maureen Murphy, The Wistar Institute, United States

Ethics

Animal experimentation: The experiment was not blind and was handled according to approved institutional animal care and use committee (IACUC) protocol (#4275R) of Tulane University School of Medicine. The maximum tumor volume per tumor allowed the IACUC committee is 1.5 cm diameter or 300 mm3 per tumor.

Version history

  1. Received: August 15, 2017
  2. Accepted: March 13, 2018
  3. Accepted Manuscript published: March 16, 2018 (version 1)
  4. Version of Record published: March 27, 2018 (version 2)
  5. Version of Record updated: April 3, 2018 (version 3)

Copyright

© 2018, Fang 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. Ziling Fang
  2. Bo Cao
  3. Jun-Ming Liao
  4. Jun Deng
  5. Kevin D Plummer
  6. Peng Liao
  7. Tao Liu
  8. Wensheng Zhang
  9. Kun Zhang
  10. Li Li
  11. David Margolin
  12. Shelya X Zeng
  13. Jianping Xiong
  14. Hua Lu
(2018)
SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer
eLife 7:e31275.
https://doi.org/10.7554/eLife.31275

Share this article

https://doi.org/10.7554/eLife.31275

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