Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells

Journal of Cell Biology - Tập 193 Số 2 - Trang 275-284 - 2011
Yoshihiro Inami1,2,3, Satoshi Waguri4,5, Ayako Sakamoto3, Tsuguka Kouno3, Kazuto Nakada6, Okio Hino1,2, Sumio Watanabe1,2, Jin Ando4,5, Manabu Iwadate4,5, Masayuki Yamamoto7, Myung‐Shik Lee8, Keiji Tanaka3, Masaaki Komatsu3
1Department of Gastroenterology and Department of Pathology and Oncology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
2Department of Pathology and Oncology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan 2 and 3
3Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan 1
4Department of Anatomy and Histology and Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan
5Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan 4 and 5
6Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan 6
7Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan 7
8Department of Medicine, Samsung Medical Center, Kangnam-ku, Seoul 135-710, Korea 8

Tóm tắt

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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Journal of Cell Biology

Tập 193 Số 2

275-284

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