Abstract
Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.
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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Autophagy*
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Autophagy-Related Protein 7 / genetics
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Autophagy-Related Protein 7 / metabolism
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Carcinogenesis
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Cell Cycle Proteins
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Cell Differentiation
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Female
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Hepatocytes / cytology*
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Hepatocytes / metabolism
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Humans
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Liver / cytology
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Liver / metabolism*
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Liver / pathology
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / physiopathology*
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Male
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Mice
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Proteolysis
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Transcription Factors
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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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Transcription Factors
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YAP-Signaling Proteins
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YAP1 protein, human
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Yap1 protein, mouse
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Autophagy-Related Protein 7