Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77.
Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77.
复制标题
通过孤儿核受体 Nur77 的非基因组作用抑制 β-连环蛋白信号传导。
DOI：
10.1038/onc.2011.448
复制
发表时间：
2012-05-24
期刊：
影响因子：
8
通讯作者：
Zhang, X-K
中科院分区：
文献类型：
--
作者：
Sun, Z.;Cao, X.;Jiang, M-M;Qiu, Y.;Zhou, H.;Chen, L.;Qin, B.;Wu, H.;Jiang, F.;Chen, J.;Liu, J.;Dai, Y.;Chen, H-F;Hu, Q-Y;Wu, Z.;Zeng, J-Z;Yao, X-S;Zhang, X-K
由于β-连环蛋白的调节蛋白包括APC和P53的突变，导致其代谢紊乱，参与了癌症的发病机制。因此，人们正在加紧努力寻找替代方法来减少癌细胞中异常激活的β-连环蛋白。Nur77是核受体超家族的孤儿成员，在癌细胞的生长和凋亡中发挥作用。在这里，我们报道了Nur77可以通过蛋白酶体降解途径诱导β-连环蛋白的降解来抑制β-连环蛋白的转录活性，该途径不依赖于β和SIAH-1。NUR77诱导β-连环蛋白降解既需要参与NUR77泛素化的N端区域，也需要负责β-连环蛋白结合的C端区域。NUR77/ΔDBD是一个缺失NUR77结合结构域的突变体，它存在于细胞质中，与β-连环蛋白相互作用，并诱导β-连环蛋白的降解，表明NUR77介导的β-连环蛋白的降解不依赖于其结合和反式激活，可能发生在细胞质中。此外，我们鉴定了两个洋地黄类化合物，H-9和ATE-I2-b4，它们在体外和动物体内都能有效地诱导表达突变型APC蛋白的SW620结肠癌细胞中Nur77的表达和β-连环蛋白的降解。DLC诱导的Nur77蛋白主要存在于胞浆中，依赖于CRM1的核输出抑制剂瘦素B或Jun氨基末端激酶抑制剂抑制Nur77核输出，阻止了DLC诱导β-连环蛋白降解的作用。综上所述，我们的结果表明，胞质NUR77可以通过它们的相互作用来降解β-连环蛋白，并确定H-9和ATE-I2-b4是NUR77介导的β-连环蛋白降解途径的有效激活剂。
Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including APC and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, plays a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is GSK3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA-binding and transactivation and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.
登录
查看更多内容
影响因子：
11.2
作者：
Lee SO;Abdelrahim M;Yoon K;Chintharlapalli S;Papineni S;Kim K;Wang H;Safe S
通讯作者：
Safe S
见血封喉中的强心内酯作为有效的选择性 Nur77 调节剂
影响因子：
1.7
作者：
Jiang, Miao-Miao;Dai, Yi;Yao, Xin-Sheng
通讯作者：
Yao, Xin-Sheng
影响因子：
11.2
作者：
Ke, N;Claassen, G;Li, QX
通讯作者：
Li, QX
DOI：
10.1073/pnas.96.11.6273
发表时间：
1999-05-25
影响因子：
11.1
作者：
Liu, CM;Kato, Y;He, X
通讯作者：
He, X
影响因子：
5.3
作者：
Kolluri, SK;Bruey-Sedano, N;Zhang, XK
通讯作者：
Zhang, XK