title: Nuclear translocation of fibroblast growth factor-2 (FGF2) is regulated by Karyopherin-β2 and Ran GTPase in human glioblastoma cells.
abstract: Human glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Fibroblast growth factor-2 (FGF2) belongs to the FGF superfamily and functions as a potential oncoprotein in GBM. FGF2 has low molecular weight (18K) and high molecular weight (HMW) isoforms. Nuclear accumulation of HMW-FGF2 strongly promotes glioblastoma cell proliferation, yet mechanism governing such cellular distribution remains unexplored. We investigated the mechanisms regulating FGF2 cellular localization in T98G human brain glioblastoma cells. We found HMW-FGF2, but not 18K-FGF2, is primarily located in the nucleus and interacts with nuclear transport protein Karyopherin-β2/Transportin (Kapβ2). SiRNA-directed Kapβ2 knockdown significantly reduced HMW-FGF2's nuclear translocation. Moreover, inhibiting Ran GTPase activity also resulted in decreased HMW-FGF2 nuclear accumulation. Proliferation of T98G cells is greatly enhanced with transfections HMW-FGF2. Decreased PTEN expression and activated Akt signaling were observed upon HMW-FGF2 overexpression and might mediate pro-survival effect of FGF2. Interestingly, addition of nuclear localization signal (NLS) to 18K-FGF2 forced its nuclear import and dramatically increased cell proliferation and Akt activation. These findings demonstrated for the first time the molecular mechanisms for FGF2's nuclear import, which promotes GBM cell proliferation and survival, providing novel insights to the development of GBM treatments.
authors.affiliation: Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, The Second Hospital of Baoding City, Baoding 071051, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Physiology, Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Gengshen
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Baohua
authors.initials: B
authors.lastname: Jiao
mesh_terms: D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016543:Central Nervous System Neoplasms / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008970:Molecular Weight; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism; D014162:Transfection; D028961:beta Karyopherins / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000378:metabolism*
chemical_list: C120587:RAN protein, human; D034741:RNA, Small Interfering; C108121:TNPO1 protein, human; D013873:Thionucleotides; D028961:beta Karyopherins; D016222:Fibroblast Growth Factor 2; D006153:Guanosine Diphosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C023427:guanosine 5'-O-(2-thiodiphosphate); D020931:ran GTP-Binding Protein
keywords: fibroblast growth factor (FGF); glioblastoma; nuclear translocation; phosphatase and tensin homolog (PTEN); small GTPase