The Ras homolog (Rho) small GTPases, via their role in regulating the actin cytoskeleton, coordinate diverse cellular functions including cell morphology, adhesion and motility, as well as cell cycle progression, survival and apoptosis. The upstream regulators for many of these functions are unknown. ARHGEF17 (also known as TEM4) is a Rho family guanine nucleotide exchange factor (GEF) that been implicated in cell migration, cell-cell junction formation and the mitotic checkpoint. In this study we characterize the regulation of the cell cycle by TEM4. We demonstrate that TEM4 depleted cells exhibit multiple defects in mitotic entry and duration, spindle morphology, and spindle orientation. In addition, we find that TEM4 insufficiency leads to excessive cortical actin polymerization and cell rounding defects. Mechanistically, we demonstrate that TEM4 depleted cells delay in G1 as a consequence of elevated levels of the G1/S inhibitor p21waf1/cip1 and that TEM4 depleted cells that progress through to mitosis, do so with decreased transcription of CCNB1 and thus attenuated levels of cyclin B. Importantly, cyclin B overexpression in TEM4-depleted cells largely rescues mitotic progression and chromosome segregation defects in anaphase. Our study thus illustrates the consequences of Rho signalling imbalance on cell cycle progression and identifies TEM4 as the first GEF governing Rho GTPase-mediated regulation of G1/S.

中文翻译：

---

ARHGEF17/TEM4 通过控制 G1 进程来调节细胞周期

Ras 同系物 (Rho) 小 GTP 酶通过其调节肌动蛋白细胞骨架的作用，协调多种细胞功能，包括细胞形态、粘附和运动，以及细胞周期进程、存活和凋亡。其中许多功能的上游调节器尚不清楚。 ARHGEF17（也称为 TEM4）是一种 Rho 家族鸟嘌呤核苷酸交换因子 (GEF)，与细胞迁移、细胞间连接形成和有丝分裂检查点有关。在本研究中，我们描述了 TEM4 对细胞周期的调节。我们证明 TEM4 耗尽的细胞在有丝分裂进入和持续时间、纺锤体形态和纺锤体方向方面表现出多种缺陷。此外，我们发现 TEM4 不足会导致皮质肌动蛋白过度聚合和细胞变圆缺陷。从机制上讲，我们证明 TEM4 耗尽的细胞由于 G1/S 抑制剂 p21waf1/cip1 水平升高而导致 G1 期延迟，并且 TEM4 耗尽的细胞进入有丝分裂，同时 CCNB1 转录减少，从而减弱细胞周期蛋白水平B. 重要的是，细胞周期蛋白 B 在 TEM4 耗尽的细胞中过度表达，很大程度上可以挽救有丝分裂进展和后期染色体分离缺陷。因此，我们的研究阐明了 Rho 信号失衡对细胞周期进展的影响，并确定 TEM4 是第一个控制 Rho GTPase 介导的 G1/S 调节的 GEF。