Cyclin G2 Promotes HypoxiaDriven Local Invasion of Glioblastoma by Orchestrating Cytoskeletal Dynamics
Cyclin G2 Promotes HypoxiaDriven Local Invasion of Glioblastoma by Orchestrating Cytoskeletal Dynamics
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DOI：
10.1593/neo.131440
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发表时间：
2013-11-01
期刊：
影响因子：
4.8
通讯作者：
Matsui, Hideki
中科院分区：
文献类型：
--
作者：
Fujimura, Atsushi;Michiue, Hiroyuki;Matsui, Hideki
微环境条件如缺氧通过调节信号转导和蛋白质修饰增强恶性肿瘤（包括胶质母细胞瘤）的局部侵袭，但缺氧控制细胞骨架动力学以促进局部侵袭的机制尚不清楚。在这里，我们表明，细胞周期蛋白G2发挥关键作用，在细胞骨架动力学缺氧驱动的胶质母细胞瘤细胞的侵袭。细胞周期蛋白G2是一种缺氧诱导的细胞凋亡相关蛋白，是胶质母细胞瘤增殖所必需的。从机制上讲，细胞周期蛋白G2通过其SH3结构域结合基序将coronin招募到细胞膜上，从而促进coronin与src的限制性酪氨酸磷酸化。此外，细胞周期蛋白G2与丝状肌动蛋白相互作用，以促进膜皱褶的形成。在原发性胶质母细胞瘤中，细胞周期蛋白G2在严重缺氧的区域如pseudopalisades中大量表达，pseudopalisades由活跃迁移的胶质瘤细胞组成。此外，我们显示了达沙替尼在体外和体内对缺氧驱动的细胞周期蛋白G2参与的侵袭的有效性。我们的研究结果阐明了严重缺氧促进局部侵袭的细胞骨架调节机制，并可能为胶质母细胞瘤提供治疗靶点。
Microenvironmental conditions such as hypoxia potentiate the local invasion of malignant tumors including glioblastomas by modulating signal transduction and protein modification, yet the mechanism by which hypoxia controls cytoskeletal dynamics to promote the local invasion is not well defined. Here, we show that cyclin G2 plays pivotal roles in the cytoskeletal dynamics in hypoxia-driven invasion by glioblastoma cells. Cyclin G2 is a hypoxia-induced and cytoskeleton-associated protein and is required for glioblastoma expansion. Mechanistically, cyclin G2 recruits cortactin to the juxtamembrane through its SH3 domain-binding motif and consequently promotes the restricted tyrosine phosphorylation of cortactin in concert with src. Moreover, cyclin G2 interacts with filamentous actin to facilitate the formation of membrane ruffles. In primary glioblastoma, cyclin G2 is abundantly expressed in severely hypoxic regions such as pseudopalisades, which consist of actively migrating glioma cells. Furthermore, we show the effectiveness of dasatinib against hypoxia-driven, cyclin G2-involved invasion in vitro and in vivo. Our findings elucidate the mechanism of cytoskeletal regulation by which severe hypoxia promotes the local invasion and may provide a therapeutic target in glioblastoma.