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  • Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.

Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.

The Journal of cell biology (2011-04-13)
Yoshihiro Inami, Satoshi Waguri, Ayako Sakamoto, Tsuguka Kouno, Kazuto Nakada, Okio Hino, Sumio Watanabe, Jin Ando, Manabu Iwadate, Masayuki Yamamoto, Myung-Shik Lee, Keiji Tanaka, Masaaki Komatsu
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.

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CompoZr® Custom Zinc Finger Nuclease (ZFN), ZFN plasmid and mRNA