title: Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.
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.
authors.affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Inami
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.forename: Ayako
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Tsuguka
authors.initials: T
authors.lastname: Kouno
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
authors.forename: Jin
authors.initials: J
authors.lastname: Ando
authors.forename: Manabu
authors.initials: M
authors.lastname: Iwadate
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502661:Atg7 protein, mouse; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D000071193:Autophagy-Related Protein 7