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Two-signal requirement for growth-promoting function of Yap in hepatocytes

  1. Tian Su
  2. Tanya Bondar
  3. Xu Zhou
  4. Cuiling Zhang
  5. Hang He
  6. Ruslan Medzhitov  Is a corresponding author
  1. Howard Hughes Medical Institute, Yale University School of Medicine, United States
  2. College of Life Sciences, Peking University, China
Research Article
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Cite this article as: eLife 2015;4:e02948 doi: 10.7554/eLife.02948

Abstract

The transcriptional coactivator Yes-associated protein (Yap) promotes proliferation and inhibits apoptosis, suggesting that Yap functions as an oncogene. Most oncogenes, however, require a combination of at least two signals to promote proliferation. Here we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model, we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion, as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth, a second signal provided by tissue damage or inflammation is required. In response to liver injury, Yap drives clonal expansion, suppresses hepatocyte differentiation and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair.

Article and author information

Author details

  1. Tian Su

    Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Tanya Bondar

    Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xu Zhou

    Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Cuiling Zhang

    Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hang He

    Peking-Yale Joint Center for Plant Molecular Genetics and Agro-Biotechnology, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Ruslan Medzhitov

    Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    For correspondence
    ruslan.medzhitov@yale.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal experiments were performed with approval by the Institutional Animal Care and Use Committee of Yale University (protocol # 2014-08006).

Reviewing Editor

  1. Alejandro Sánchez Alvarado, Howard Hughes Medical Institute, Stowers Institute for Medical Research, United States

Publication history

  1. Received: March 29, 2014
  2. Accepted: February 9, 2015
  3. Accepted Manuscript published: February 10, 2015 (version 1)
  4. Version of Record published: March 18, 2015 (version 2)

Copyright

© 2015, Su 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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