Lee Mi-Jee, Kim Mi-Yeon, Mo Jung-Soon, Ann Eun-Jung, Seo Mi-Sun, Hong Ji-Ae, Kim Yong-Chul, Park Hee-Sae
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Yongbong-dong, Gwangju, Republic of Korea.
Cancer Lett. 2008 Jul 8;265(2):215-25. doi: 10.1016/j.canlet.2008.02.013. Epub 2008 Mar 17.
Notch proteins perform a critical function in cell-fate decisions and in differentiation. In this study, we determined that indirubin-3'-monoxime reduced Notch1 signaling to a remarkable extent. Indirubin-3'-monoxime has been shown to inhibit both constitutive active mutants of Notch1 and Notch1-IC-mediated transactivation activity. However, in such cases, neither the Notch cleavage pattern nor the protein stability of Notch1-IC was determined to have been significantly altered. Indirubin-3'-monoxime suppresses Notch1 transcriptional activity via the dissociation of the Notch1-IC-RBP-Jk complex. Notably, the transcriptional activity of Notch1-IC was not suppressed significantly in the GSK-3beta null cells by indirubin-3'-monoxime as compared to what was observed with GSK-3beta wild-type cells. In the previous study, we synthesized a series of indirubin derivatives. Interestingly, some of these indirubin derivatives were characterized as potent inhibitors of Notch1 signaling. Taken together, the results of this study indicate that indirubin-3'-monoxime downregulated Notch1 signaling in a GSK-3beta-dependent and proteosomal degradation-independent manner.
Notch蛋白在细胞命运决定和分化过程中发挥着关键作用。在本研究中，我们确定靛玉红-3'-单肟能显著降低Notch1信号传导。靛玉红-3'-单肟已被证明可抑制Notch1的组成型活性突变体以及Notch1-IC介导的反式激活活性。然而，在这些情况下，未确定Notch的切割模式或Notch1-IC的蛋白质稳定性有显著改变。靛玉红-3'-单肟通过Notch1-IC-RBP-Jk复合物的解离来抑制Notch1转录活性。值得注意的是，与GSK-3β野生型细胞相比，靛玉红-3'-单肟在GSK-3β缺失细胞中对Notch1-IC转录活性的抑制作用并不显著。在先前的研究中，我们合成了一系列靛玉红衍生物。有趣的是，其中一些靛玉红衍生物被鉴定为Notch1信号的有效抑制剂。综上所述，本研究结果表明靛玉红-3'-单肟以GSK-3β依赖性和蛋白酶体降解非依赖性方式下调Notch1信号传导。
