Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.
Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.
复制标题
NRF2通过p62在肝细胞癌细胞中的持续激活。
DOI：
10.1083/jcb.201102031
复制
发表时间：
2011-04-18
期刊：
影响因子：
--
通讯作者：
Komatsu M
中科院分区：
文献类型：
--
作者：
Inami Y;Waguri S;Sakamoto A;Kouno T;Nakada K;Hino O;Watanabe S;Ando J;Iwadate M;Yamamoto M;Lee MS;Tanaka K;Komatsu M
受损的自噬稳定p62并通过激活Nrf 2转录因子促进肿瘤发生。自噬的抑制总是伴随着选择性自噬底物p62的显著积累。由于p62与Keap 1上的Nrf 2结合位点相互作用，Keap 1是一种基于Cullin 3的泛素连接酶衔接蛋白，自噬缺陷导致Nrf 2-Keap 1相互作用的竞争性抑制，导致Nrf 2稳定，随后Nrf 2靶基因的转录激活。在此，我们发现肝脏特异性自噬缺陷小鼠的腺瘤与p62和Keap 1阳性细胞聚集体的形成和Nrf 2靶点的诱导有关。重要的是，在超过25%的人肝细胞癌（HCC）中鉴定出类似的聚集体，并且在大多数这些肿瘤中识别出Nrf 2靶基因的诱导。在HCC细胞系中靶向p62的基因显著地消除了锚定非依赖性生长，而p62的强制表达，而不是Keap 1相互作用缺陷突变体，导致生长缺陷的恢复。这些结果表明，参与持续激活Nrf 2通过积累的p62在肝癌的发展。
Impaired autophagy stabilizes p62 and promotes tumorigenesis through activation of the Nrf2 transcription factor. 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.
登录
查看更多内容
影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
64.5
作者：
Jin, Zhaoyu;Li, Yun;Ashkenazi, Avi
通讯作者：
Ashkenazi, Avi
影响因子：
50.3
作者：
Duran, Angeles;Linares, Juan F.;Moscat, Jorge
通讯作者：
Moscat, Jorge
影响因子：
16
作者：
Padmanabhan, B;Tong, KI;Yamamoto, M
通讯作者：
Yamamoto, M
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T