Journal
JOURNAL OF CELL BIOLOGY
Volume 193, Issue 2, Pages 275-284Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201102031
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Funding Program for Next Generation World-Leading Researchers
- National Research Foundation of Korea
- National Research Foundation of Korea [2010-00347, 2008-2004090] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Grants-in-Aid for Scientific Research [19GS0312, 21659045, 22650091, 21390234] Funding Source: KAKEN
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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.
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