title: Two-signal requirement for growth-promoting function of Yap in hepatocytes.
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.
authors: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors: Tian
authors: T
authors: Su
authors: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors: Tanya
authors: T
authors: Bondar
authors: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors: Xu
authors: X
authors: Zhou
authors: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors: Cuiling
authors: C
authors: Zhang
authors: 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.
authors: Hang
authors: H
authors: He
authors: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors: Ruslan
authors: R
authors: Medzhitov
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D002251:Carbon Tetrachloride
keywords: cell biology; growth control; hippo; inflammation; mouse