Chemical enhancers of cytokine signaling that suppress microfilament turnover and tumor cell growth.
Chemical enhancers of cytokine signaling that suppress microfilament turnover and tumor cell growth.
复制标题
细胞因子信号传导的化学增强剂，抑制微丝更新和肿瘤细胞生长。
作者：
Hyun;E. Partridge;P. Cheung;J. Pawling;R. Donovan;J. Wrana;J. Dennis
转化生长因子-β(TGF-β)家族的细胞因子调节后生动物的细胞增殖、形态发生和特殊细胞功能。在这里，我们使用基于细胞的方法来检测Smad2/3核转位，以筛选NMuMG上皮细胞中转化生长因子-β信号的修饰物的复合库。我们确定了5个具有2-(苯亚甲基)丙二酸二乙酯(DAM)核心结构和D(50)值1~4微摩尔/L的转化生长因子-β信号增强剂。利用内吞作用受体加速丢失的突变表型，我们确定了转化生长因子-β和表皮生长因子(EGF)对转化生长因子-β(-/-)癌细胞的敏感性。在mGat5突变型和野生型癌细胞中，DAM-1976分别增强和延长了依赖于转化生长因子β和表皮生长因子的Smad2/3和ERK的激活。DAM-1976减少了配体依赖的EGF受体内吞作用、肌动蛋白微丝周转和细胞扩散，表明该化合物减弱了囊泡的运输。细胞内信号的过度激活有可能抑制肿瘤细胞的生长，在这方面，DAM-1976代表了一种新的药效团，它增加了Smad2/3和Erk的基础激活，抑制了微丝重塑，并抑制了癌细胞的生长。
The transforming growth factor-beta (TGF-beta) family of cytokines regulates cell proliferation, morphogenesis, and specialized cell functions in metazoans. Herein, we screened a compound library for modifiers of TGF-beta signaling in NMuMG epithelial cells using a cell-based assay to measure Smad2/3 nuclear translocation. We identified five enhancers of TGF-beta signaling that share a core structure of diethyl 2-(anilinomethylene)malonate (DAM), and D(50) values of 1 to 4 micromol/L. Taking advantage of the Mgat5 mutant phenotype of accelerated receptor loss to endocytosis, we determined that DAM-1976 restored the sensitivity of Mgat5(-/-) carcinoma cells to both TGF-beta and epidermal growth factor (EGF). In Mgat5 mutant and wild-type carcinoma cells, DAM-1976 enhanced and prolonged TGF-beta- and EGF-dependent Smad2/3 and Erk activation, respectively. DAM-1976 reduced ligand-dependent EGF receptor endocytosis, actin microfilament turnover, and cell spreading, suggesting that the compound attenuates vesicular trafficking. Hyperactivation of intracellular signaling has the potential to suppress tumor cell growth and, in this regard, DAM-1976 represents a new pharmacophore that increases basal activation of Smad2/3 and Erk, inhibits microfilament remodeling, and suppresses carcinoma cell growth.
影响因子：
20.3
作者：
Li, Z;Kim, ES;Bearer, EL
通讯作者：
Bearer, EL