Abstract
The tumor suppressor cylindromatosis (CYLD) inhibits the NFκB and mitogen-activated protein kinase (MAPK) activation pathways by deubiquitinating upstream regulatory factors. Here we show that liver-specific disruption of CYLD triggers hepatocyte cell death in the periportal area via spontaneous and chronic activation of TGF-β activated kinase 1 (TAK1) and c-Jun N-terminal kinase (JNK). This is followed by hepatic stellate cell and Kupffer cell activation, which promotes progressive fibrosis, inflammation, tumor necrosis factor (TNF) production, and expansion of hepatocyte apoptosis toward the central veins. At later stages, compensatory proliferation results in the development of cancer foci featuring re-expression of oncofetal hepatic and stem cell-specific genes. The results demonstrate that, in the liver, CYLD acts as an important regulator of hepatocyte homeostasis, protecting cells from spontaneous apoptosis by preventing uncontrolled TAK1 and JNK activation.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics*
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Blotting, Western
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Comparative Genomic Hybridization
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Cysteine Endopeptidases / genetics*
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Cysteine Endopeptidases / metabolism
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Deubiquitinating Enzyme CYLD
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Enzyme Activation / drug effects
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Fibrosis / genetics
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Fibrosis / metabolism
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Gene Expression Profiling
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Hepatocytes / metabolism*
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Hepatocytes / pathology
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Immunohistochemistry
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Inflammation / genetics
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Inflammation / metabolism
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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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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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Reverse Transcriptase Polymerase Chain Reaction
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Time Factors
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Proteins
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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CYLD protein, mouse
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Deubiquitinating Enzyme CYLD
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Cysteine Endopeptidases