Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells.
Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells.
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DOI：
10.1111/cas.14637
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发表时间：
2020-11
期刊：
影响因子：
5.7
通讯作者：
Takahashi M
中科院分区：
文献类型：
--
作者：
Chen C;Enomoto A;Weng L;Taki T;Shiraki Y;Mii S;Ichihara R;Kanda M;Koike M;Kodera Y;Takahashi M
肌动蛋白结合蛋白Girdin是一种枢纽蛋白，与多种蛋白相互作用，调节癌细胞的运动和Akt和三聚体G蛋白信号。Girdin表达与多种人类癌症的不良预后相关。然而，这些发现并不普遍，因为它们取决于研究条件。这些数据表明，必须重新考虑Girdin功能的多个方面及其在肿瘤细胞对抗癌治疗反应中的作用。在本研究中，我们发现Girdin参与了DNA损伤诱导的癌细胞凋亡。高Girdin表达的食管癌细胞系与低Girdin表达的食管癌细胞系相比，对紫外线介导的DNA损伤表现出明显的敏感性。当内源性Girdin的转录激活由工程CRISPR/Cas9激活系统介导时，静止和迁移的HeLa癌细胞对DNA损伤的敏感性都增加了。高表达的Girdin与细胞周期进程失调、G1期和M期延长有关。这些特征伴随着p53的激活，可想而知，这增加了癌细胞对紫外线暴露的脆弱性。这些数据强调了了解影响癌细胞对治疗敏感性的复杂Girdin功能的重要性。本研究表明，Girdin过表达扰乱细胞周期分布，延长G1期和M期，并异常激活p53，从而导致对DNA损伤的敏感性增加。研究还表明，在Girdin过表达的细胞中，纺锤体检查点蛋白Mad2的上调可能与细胞周期进程失调有关。
The actin‐binding protein Girdin is a hub protein that interacts with multiple proteins to regulate motility and Akt and trimeric G protein signaling in cancer cells. Girdin expression correlates with poor outcomes in multiple human cancers. However, those findings are not universal, as they depend on study conditions. Those data suggest that multiple aspects of Girdin function and its role in tumor cell responses to anticancer therapeutics must be reconsidered. In the present study, we found that Girdin is involved in DNA damage‐induced cancer cell apoptosis. An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV‐mediated DNA damage compared to a line with low Girdin expression. When transcriptional activation of endogenous Girdin was mediated by an engineered CRISPR/Cas9 activation system, sensitivity to DNA damage increased in both stationary and migrating HeLa cancer cells. High Girdin expression was associated with dysregulated cell cycle progression and prolonged G1 and M phases. These features were accompanied by p53 activation, which conceivably increases cancer cell vulnerability to UV exposure. These data highlight the importance of understanding complex Girdin functions that influence cancer cell sensitivity to therapeutics. The present study suggests that Girdin overexpression perturbs cell cycle distribution with prolonged G1 and M phases and aberrant p53 activation, which leads to an increase in sensitivity to DNA damage. It also showed that the upregulation of the spindle checkpoint protein Mad2 in Girdin‐overexpressing cells could be involved in dysregulated cell cycle progression.
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影响因子：
64.8
作者：
Konermann S;Brigham MD;Trevino AE;Joung J;Abudayyeh OO;Barcena C;Hsu PD;Habib N;Gootenberg JS;Nishimasu H;Nureki O;Zhang F
通讯作者：
Zhang F
影响因子：
4.8
作者：
Garcia-Marcos, Mikel;Jung, Barbara H.;Ghosh, Pradipta
通讯作者：
Ghosh, Pradipta
影响因子：
4.5
作者：
Choi, Jong-Sun;Kim, Kyung Hee;Choi, Yoon-La
通讯作者：
Choi, Yoon-La
DOI：
10.1038/nrc3958
发表时间：
2015-07
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Barker HE;Paget JT;Khan AA;Harrington KJ
通讯作者：
Harrington KJ
影响因子：
10.5
作者：
DI LEONARDO, A;LINKE, SP;WAHL, GM
通讯作者：
WAHL, GM