Key role for Rac in the early transcriptional response to extracellular matrix stiffness and stiffness-dependent repression of ATF3.
Key role for Rac in the early transcriptional response to extracellular matrix stiffness and stiffness-dependent repression of ATF3.
复制标题
DOI：
10.1242/jcs.260636
复制
发表时间：
2023-10-01
影响因子：
4
通讯作者：
Assoian, Richard K.
中科院分区：
文献类型：
--
作者：
Dang, Irene;Brazzo, Joseph A.;Bae, Yongho;Assoian, Richard K.
Rho家族GTP酶Rac和Rho在将细胞外基质(ECM)中的机械信息传递到细胞中起着关键作用。Rac和Rho在调节僵硬依赖的肌动蛋白重塑、增殖和运动性方面的作用已被熟知。然而，人们对这些GTP酶在刚性依赖的转录中的相对作用知之甚少，特别是在全基因组水平上。在这里，我们选择性地抑制在可变形底物上培养的小鼠胚胎成纤维细胞中的Rac和Rho，并使用RNA测序来阐明和比较这些GTP酶在细胞外基质僵硬的早期转录反应中的作用。令人惊讶的是，我们发现在对ECM刚性的初始转录反应中，Rac的依赖于硬度的激活比Rho占优势。我们还发现激活转录因子3(ATF3)是僵硬和RAC介导的信号转导的主要靶点，并表明ECM僵硬对ATF3的抑制有助于解释RAC的僵硬依赖激活如何导致细胞周期蛋白D1的诱导。摘要：Rac在细胞外基质刚性的初始转录反应中起主要作用，并介导ATF3的刚性依赖的抑制，导致细胞周期蛋白D1的诱导。
The Rho family GTPases Rac and Rho play critical roles in transmitting mechanical information contained within the extracellular matrix (ECM) to the cell. Rac and Rho have well-described roles in regulating stiffness-dependent actin remodeling, proliferation and motility. However, much less is known about the relative roles of these GTPases in stiffness-dependent transcription, particularly at the genome-wide level. Here, we selectively inhibited Rac and Rho in mouse embryonic fibroblasts cultured on deformable substrata and used RNA sequencing to elucidate and compare the contribution of these GTPases to the early transcriptional response to ECM stiffness. Surprisingly, we found that the stiffness-dependent activation of Rac was dominant over Rho in the initial transcriptional response to ECM stiffness. We also identified activating transcription factor 3 (ATF3) as a major target of stiffness- and Rac-mediated signaling and show that ATF3 repression by ECM stiffness helps to explain how the stiffness-dependent activation of Rac results in the induction of cyclin D1. Summary: Rac plays a major role in the initial transcriptional response to extracellular matrix stiffness and mediates the stiffness-dependent repression of ATF3, resulting in the induction of cyclin D1.
登录
查看更多内容
影响因子：
7.2
作者：
Geiger B;Yamada KM
通讯作者：
Yamada KM
影响因子：
3.7
作者：
Burridge K;Guilluy C
通讯作者：
Guilluy C
DOI：
10.3791/2089
发表时间：
2010-08-10
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Cretu, Alexandra;Castagnino, Paola;Assoian, Richard
通讯作者：
Assoian, Richard
影响因子：
4.8
作者：
Debreceni, B;Gao, Y;Zheng, Y
通讯作者：
Zheng, Y
影响因子：
5.8
作者：
Duprez, Daniel A;Cohn, Jay N
通讯作者：
Cohn, Jay N