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Cited by 64Hippo pathway signaling and YAP/TAZLiver physiology and pathologyWnt/β-catenin signaling in development and cancer

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

Open access
Su, Tian, Bondar, Tanya, Zhou, Xu, Zhang, Cuiling, He, Hang, Medzhitov, Ruslan·2015·eLife
DOI 10.7554/elife.02948PMC PMC4363878
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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. In this study, 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.

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  • In hepatocytes, activation of YAP and TAZ cofactors has a fundamental role in the appropriate response to damage during liver fibrosis.

    “In hepatocytes, the activation of YAP and TAZ cofactors have a fundamental role in the appropriate response to damage during liver fibrosis [6, 20, 21].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [21]

    The Results section (“Yap promotes hepatocyte proliferation in response to injury,” Figure 4) reports that hepatocyte-specific Yap knockout reduced proliferation during repair after acute CCl4 injury and was associated with abnormal collagen deposition. The paper supports a role for Yap in the damage response, but these findings do not establish a role for TAZ or specifically address the response during liver fibrosis. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Su, T., Bondar, T., Zhou, X., Zhang, C., He, H., & Medzhitov, R.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Peking University (CN)
Corresponding author
Medzhitov, Ruslan
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2015-02-10
Volume
4
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.02948
PMC
PMC4363878
OpenAlex
W2163269287
Cited by
64
References
11
Citations by year
2026: 3 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 13 · 2017: 5 · 2016: 7 · 2015: 1
FWCI
4.62
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Howard Hughes Medical Institute (HHMI)
  • National Cancer Institute (NCI) (CA157461)
  • National Institute of Allergy and Infectious Diseases (NIAID) (AI046688)
  • Jane Coffin Childs Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
YAP, hepatocytes, oncogene activation, clonal expansion, apoptosis, liver injury, tissue damage, inflammation, hepatocyte differentiation, tissue homeostasis, tissue repair
MeSH terms
YAP-Signaling Proteins, Animals, Carbon Tetrachloride, Cells, Cultured, Inflammation, Liver, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Fluorescence, Phosphoproteins, Blotting, Western, Signal Transduction, Mice, Knockout, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Hepatocytes, Adaptor Proteins, Signal Transducing, Cell Proliferation, TNF-Related Apoptosis-Inducing Ligand, Chemical and Drug Induced Liver Injury

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