文章目录

FoxM1不足会过度激活Ect2-RhoA-mDia1信号，从而驱动癌症

原文发布日期：2020-10-12

英文摘要：

摘要翻译：

原文链接：

文章：

FoxM1不足会过度激活Ect2-RhoA-mDia1信号，从而驱动癌症

FoxM1 insufficiency hyperactivates Ect2–RhoA–mDia1 signaling to drive cancer

原文发布日期：2020-10-12

英文摘要：

FoxM1 activates genes that regulate S–G2–M cell-cycle progression and, when overexpressed, is associated with poor clinical outcome in multiple cancers. Here we identify FoxM1 as a tumor suppressor in mice that, through its N-terminal domain, binds to and inhibits Ect2 to limit the activity of RhoA GTPase and its effector mDia1, a catalyst of cortical actin nucleation. FoxM1 insufficiency impedes centrosome movement through excessive cortical actin polymerization, thereby causing the formation of nonperpendicular mitotic spindles that missegregate chromosomes and drive tumorigenesis in mice. Importantly, low FOXM1 expression correlates with RhoA GTPase hyperactivity in multiple human cancer types, indicating that suppression of the newly discovered Ect2–RhoA–mDia1 oncogenic axis by FoxM1 is clinically relevant. Furthermore, by dissecting the domain requirements through which FoxM1 inhibits Ect2 guanine nucleotide-exchange factor activity, we provide mechanistic insight for the development of pharmacological approaches that target protumorigenic RhoA activity.

摘要翻译：

在本研究中，我们识别了狐狸M1（FoxM1）作为小鼠中的 tumor 抑 suppressing 器。通过其 N-端区域，它与 Ect2 相联系并抑制 RhoA GTPase 的活动及其效应蛋白 mDia1，从而限制了这些 GTPase 的活性，后者是 cortical 蛋白质聚集体的核酶促反应催化剂。当 FoxM1 欠乏时，这会阻碍中心体通过过度聚集体蛋白质导致细胞异常分裂，并最终导致鼠的肿瘤发生。重要的是，我们发现，在多种人类癌症中，FoxM1 表达水平降低与 RhoA GTPase 过度活化相关联，这表明通过抑制新型 Ect2-RhoA-mDia1 癌ogenic 轴，使用具有 FoxM1 的药物治疗可能具有临床意义。此外，通过对 FoxM1 摒弃过程中涉及的信号通路进行了分子机制分析，我们为靶向原癌性的 RhoA 活性开发了潜在的药物提供了机理见解。