ndole-derived compound SIS3 targets a subset of activated Smad complexes.
ndole-derived compound SIS3 targets a subset of activated Smad complexes.
复制标题
吲哚衍生化合物 SIS3 靶向激活的 Smad 复合物的子集。
DOI：
10.1093/jb/mvac104
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Miyazawa K.
中科院分区：
文献类型：
--
作者：
toh Y;Sawaguchi T;Fu H;Omata C;Saitoh M;Miyazawa K.
Smad 2和Smad 3是受体调节的Smad蛋白，其传递来自属于转化生长因子（TGF）-β家族的细胞因子的信号，其对于成人组织稳态至关重要。这些蛋白质的过度活化常常引起病理状况的发展。据报道，Smad 3介导TGF-β诱导的纤维化。虽然各种潜在的Smad 3特异性抑制剂正在开发中，但其特异性和作用机制仍在很大程度上未知。本研究的目的是建立一个生物化学平台，监测Smad 2或Smad 3依赖的TGF-β信号转导使用SMAD 2，SMAD 3和SMAD 2/3敲除细胞系与TGF-β依赖的荧光素酶报告基因和Smad突变蛋白。使用该平台，观察到广泛用作特异性Smad 3抑制剂的吲哚衍生化合物SIS 3优先抑制活化的Smad复合物的子集。然而，其抑制并不有利于Smad 3信号转导超过Smad 2信号转导。这些发现表明，SIS 3可以用作探针来检查诱导基因表达的Smad信号转导的异质性。然而，应避免将其用作Smad 3特异性抑制剂。
Smad2 and Smad3 are receptor-regulated Smad proteins that transmit signals from cytokines belonging to the transforming growth factor (TGF)-β family, which are vital for adult tissue homeostasis. The overactivation of such proteins often engenders the development of pathological conditions. Smad3 reportedly mediates TGF-β–induced fibrosis. Although various potential Smad3-specific inhibitors are being developed, their specificity and action mechanisms remain largely unknown. This study aimed to establish a biochemical platform to monitor Smad2- or Smad3-dependent TGF-β signaling usingSMAD2,SMAD3andSMAD2/3knockout cell lines alongside TGF-β–dependent luciferase reporters and Smad mutant proteins. Using this platform, SIS3, an indole-derived compound widely used as a specific Smad3 inhibitor, was observed to preferentially suppress a subset of activated Smad complexes. However, its inhibition did not favor Smad3 signaling over Smad2 signaling. These findings indicate that SIS3 can be employed as a probe to examine the heterogeneous nature of Smad signaling that induces gene expression. However, its use as a Smad3-specific inhibitor should be avoided.