Cyclin G2 promotes hypoxia-driven local invasion of glioblastoma by orchestrating cytoskeletal dynamics

Atsushi Fujimura, Michiue Hiroyuki, Yan Cheng, Atsuhito Uneda, Yasunari Tani, Tei Ichi Nishiki, Tomotsugu Ichikawa, Fan Yan Wei, Kazuhito Tomizawa, Hideki Matsui

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1272-1281
Number of pages10
JournalNeoplasia (United States)
Volume15
Issue number11
DOIs
Publication statusPublished - Nov 2013

ASJC Scopus subject areas

  • Cancer Research

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    Fujimura, A., Hiroyuki, M., Cheng, Y., Uneda, A., Tani, Y., Nishiki, T. I., Ichikawa, T., Wei, F. Y., Tomizawa, K., & Matsui, H. (2013). Cyclin G2 promotes hypoxia-driven local invasion of glioblastoma by orchestrating cytoskeletal dynamics. Neoplasia (United States), 15(11), 1272-1281. https://doi.org/10.1593/neo.131440