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- Title
Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.
- Authors
Inami, Yoshihiro; Waguri, Satoshi; Sakamoto, Ayako; Kouno, Tsuguka; Nakada, Kazuto; Hino, Okio; Watanabe, Sumio; Ando, Jin; Iwadate, Manabu; Yamamoto, Masayuki; Myung-Shik Lee; Tanaka, Keiji; Komatsu, Masaaki
- 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.
- Subjects
AUTOPHAGY; BINDING sites; PROTEINS; GENETIC transcription; LIVER cancer; CELL lines; LABORATORY mice
- Publication
Journal of Cell Biology, 2011, Vol 193, Issue 2, p275
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.201102031