Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells

DOI DOI PDF PubMed 被引用文献77件 参考文献46件 オープンアクセス
  • Yoshihiro Inami
    Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan 1
  • Satoshi Waguri
    Department of Anatomy and Histology 4 and 5
  • Ayako Sakamoto
    Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan 1
  • Tsuguka Kouno
    Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan 1
  • Kazuto Nakada
    Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan 6
  • Okio Hino
    Department of Gastroenterology 2 and 3
  • Sumio Watanabe
    Department of Gastroenterology 2 and 3
  • Jin Ando
    Department of Anatomy and Histology 4 and 5
  • Manabu Iwadate
    Department of Anatomy and Histology 4 and 5
  • Masayuki Yamamoto
    Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan 7
  • Myung-Shik Lee
    Department of Medicine, Samsung Medical Center, Kangnam-ku, Seoul 135-710, Korea 8
  • Keiji Tanaka
    Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan 1
  • Masaaki Komatsu
    Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan 1

書誌事項

公開日
2011-04-11
資源種別
journal article
DOI
  • 10.1083/jcb.201102031
  • 10.1084/jem2085oia12
公開者
Rockefeller University Press

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<jats:p>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.</jats:p>

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