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.
Keywords:
cell biology; growth control; hippo; inflammation; mouse.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Blotting, Western
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Carbon Tetrachloride / toxicity
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Cell Cycle Proteins
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Cell Proliferation / genetics*
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Cells, Cultured
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Chemical and Drug Induced Liver Injury / etiology
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Chemical and Drug Induced Liver Injury / genetics
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Chemical and Drug Induced Liver Injury / metabolism
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Gene Expression Profiling
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Hepatocytes / drug effects
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Hepatocytes / metabolism*
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Inflammation / genetics
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Inflammation / metabolism
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Liver / drug effects
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Liver / metabolism
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Microscopy, Fluorescence
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics*
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Phosphoproteins
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TNF-Related Apoptosis-Inducing Ligand
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YAP-Signaling Proteins
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Yap1 protein, mouse
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Carbon Tetrachloride