Abstract
Suppression of autophagy is always accompanied by marked accumulation of p62, a selective autophagy substrate. Because p62 interacts with the Nrf2-binding site on Keap1, which is a Cullin 3-based ubiquitin ligase adapter protein, autophagy deficiency causes competitive inhibition of the Nrf2-Keap1 interaction, resulting in stabilization of Nrf2 followed by transcriptional activation of Nrf2 target genes. Herein, we show that liver-specific autophagy-deficient mice harbor adenomas linked to both the formation of p62- and Keap1-positive cellular aggregates and induction of Nrf2 targets. Importantly, similar aggregates were identified in more than 25% of human hepatocellular carcinomas (HCC), and induction of Nrf2 target genes was recognized in most of these tumors. Gene targeting of p62 in an HCC cell line markedly abrogates the anchorage-independent growth, whereas forced expression of p62, but not a Keap1 interaction-defective mutant, resulted in recovery of the growth defect. These results indicate the involvement of persistent activation of Nrf2 through the accumulation of p62 in hepatoma development.
Publication types
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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
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cytoskeletal Proteins / metabolism
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Female
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Kelch-Like ECH-Associated Protein 1
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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Male
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Middle Aged
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NF-E2-Related Factor 2 / metabolism*
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Sequestosome-1 Protein
Substances
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Adaptor Proteins, Signal Transducing
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Atg7 protein, mouse
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Cytoskeletal Proteins
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Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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KEAP1 protein, human
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Keap1 protein, mouse
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Kelch-Like ECH-Associated Protein 1
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Microtubule-Associated Proteins
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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Nfe2l2 protein, mouse
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SQSTM1 protein, human
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Sequestosome-1 Protein
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Sqstm1 protein, mouse
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Autophagy-Related Protein 7