1. Cancer Biology
  2. Cell Biology
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TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions

  1. Raffaella Sordella  Is a corresponding author
  2. Nitin H Shirole
  3. Debjani Pal
  4. Edward R Kastenhuber
  5. Serif Senturk
  6. Joseph Boroda
  7. Paola Pisterzi
  8. Madison Miller
  9. Gustavo Munoz
  10. Marko Anderluh
  11. Marc Ladanyi
  12. Scott W Lowe
  1. Cold Spring Harbor Laboratory, United States
  2. Memorial Sloan Kettering Cancer Center, United States
  3. University of Ljubljana, Slovenia
Research Article
  • Cited 24
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Cite this article as: eLife 2016;5:e17929 doi: 10.7554/eLife.17929

Abstract

TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.

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The following previously published data sets were used

Article and author information

Author details

  1. Raffaella Sordella

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    For correspondence
    sordella@cshl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9745-1227
  2. Nitin H Shirole

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Debjani Pal

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Edward R Kastenhuber

    Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Serif Senturk

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Joseph Boroda

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Paola Pisterzi

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Madison Miller

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Gustavo Munoz

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Marko Anderluh

    Department of Medicinal Chemistry, University of Ljubljana, Ljubljana, Slovenia
    Competing interests
    The authors declare that no competing interests exist.
  11. Marc Ladanyi

    Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Scott W Lowe

    Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Cancer Institute (NCI P01 CA129243-06)

  • Raffaella Sordella
  • Marc Ladanyi
  • Scott W Lowe

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

Ethics

Animal experimentation: All animal experiments were performed in accordance with National Research Council's Guide for the Care and Use of Laboratory Animals. Protocols were approved by the Cold Spring Harbor Laboratory Animal Care and Use Committee (933922-1 Development of mouse models to study human lung cancer - integrated protocols).

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado School of Medicine, United States

Publication history

  1. Received: May 18, 2016
  2. Accepted: October 17, 2016
  3. Accepted Manuscript published: October 19, 2016 (version 1)
  4. Accepted Manuscript updated: October 24, 2016 (version 2)
  5. Version of Record published: November 2, 2016 (version 3)
  6. Version of Record updated: February 1, 2017 (version 4)

Copyright

© 2016, Sordella 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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Further reading

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