Myocardin related transcription factors are required for coordinated cell cycle progression
Myocardin related transcription factors are required for coordinated cell cycle progression
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DOI：
10.4161/cc.24839
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发表时间：
2013-06
期刊：
影响因子：
4.3
通讯作者：
D. Shaposhnikov;C. Kuffer;Z. Storchová;G. Posern
中科院分区：
文献类型：
--
作者：
D. Shaposhnikov;C. Kuffer;Z. Storchová;G. Posern
心肌素相关转录因子A和B （MRTFs）激活血清反应因子驱动的转录，响应Rho信号和肌动蛋白动力学的变化。心肌素和mrtf在一系列细胞类型的抗增殖作用中有牵连。然而，确切的机制仍然难以捉摸。我们在NIH 3T3成纤维细胞中双敲低MRTF-A和MRTF-B来评估其对细胞周期进展和增殖的影响。我们发现，mrtf的短暂耗尽具有适度的抗增殖作用，并影响正常细胞周期的进展，导致正常生长条件下的G1期显着缩短，S期和G2期略微延长。在血清饥饿条件下，我们观察到异常进入S期和G2期，没有随后的细胞分裂。这伴随着cyclin- cdk抑制剂p27Kip1、p18Ink4c和19Ink4d的下调以及p21Waf1和cyclin D1的上调。延长敲低导致微核形成增加，而mrtf稳定耗尽的细胞倾向于成为非整倍体和多倍体。因此，在成纤维细胞中，mrtf是精确的细胞周期进程和维持基因组稳定性所必需的。
Myocardin related transcription factors A and B (MRTFs) activate serum response factor-driven transcription in response to Rho signaling and changes in actin dynamics. Myocardin and MRTFs have been implicated in anti-proliferative effects on a range of cell types. The precise mechanisms, however, remained elusive. We employed double knockdown of MRTF-A and MRTF-B in NIH 3T3 fibroblasts to evaluate its effects on cell cycle progression and proliferation. We show that transient depletion of MRTFs conveys a modest anti-proliferative effect and impinges on normal cell cycle progression, resulting in significantly shortened G1 phase and slightly extended S and G2 phase under normal growth conditions. Under serum-starved conditions we observed aberrant entry into the S and G2 phases without subsequent cell division. This was accompanied by downregulation of cyclin-CDK inhibitors p27Kip1, p18Ink4c and 19Ink4d as well as upregulation of p21Waf1 and cyclin D1. Extended knockdown led to increased formation of micronuclei, while cells stably depleted of MRTFs tend to become aneuploid and polyploid. Thus, MRTFs are required for accurate cell cycle progression and maintenance of genomic stability in fibroblast cells.