| First Author | Inami Y | Year | 2011 |
| Journal | J Cell Biol | Volume | 193 |
| Issue | 2 | Pages | 275-84 |
| PubMed ID | 21482715 | Mgi Jnum | J:177008 |
| Mgi Id | MGI:5293292 | Doi | 10.1083/jcb.201102031 |
| Citation | Inami Y, et al. (2011) Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol 193(2):275-84 |
| abstractText | 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. |
