title: Cyclin G2 promotes hypoxia-driven local invasion of glioblastoma by orchestrating cytoskeletal dynamics.
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.
authors: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan ; Advanced Research Training Program, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors: Atsushi
authors: A
authors: Fujimura
authors: Hiroyuki
authors: H
authors: Michiue
authors: Yan
authors: Y
authors: Cheng
authors: Atsuhito
authors: A
authors: Uneda
authors: Yasunari
authors: Y
authors: Tani
authors: Tei-ichi
authors: T
authors: Nishiki
authors: Tomotsugu
authors: T
authors: Ichikawa
authors: Fan-Yan
authors: FY
authors: Wei
authors: Kazuhito
authors: K
authors: Tomizawa
authors: Hideki
authors: H
authors: Matsui
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D056767:Cyclin G2 / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D056767:Cyclin G2; D008840:Microfilament Proteins; D014443:Tyrosine