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Start Over Author "Symons MH" Topic guanine nucleotide exchange factors
2 results on '"Symons MH"'

1. SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide.

Author

Ensign SP, Roos A, Mathews IT, Dhruv HD, Tuncali S, Sarkaria JN, Symons MH, Loftus JC, Berens ME, and Tran NL

Subjects
Brain Neoplasms genetics, Cell Line, Tumor, Cell Survival drug effects, Cytokine TWEAK, DNA Repair drug effects, Dacarbazine pharmacology, Glioblastoma genetics, Guanine Nucleotide Exchange Factors genetics, Humans, NF-kappa B genetics, Receptors, Tumor Necrosis Factor genetics, Receptors, Tumor Necrosis Factor metabolism, Signal Transduction, TWEAK Receptor, Temozolomide, Tumor Necrosis Factors genetics, Tumor Necrosis Factors metabolism, Up-Regulation, Antineoplastic Agents, Alkylating pharmacology, Brain Neoplasms metabolism, Dacarbazine analogs & derivatives, Drug Resistance, Neoplasm, Glioblastoma metabolism, Guanine Nucleotide Exchange Factors metabolism
Abstract

Unlabelled: Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide, GB tumors develop treatment resistance and ultimately recur. Impaired response to treatment occurs rapidly, conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance to develop targeted therapies to combat this refractory disease. Previous observations indicated that SGEF (ARHGEF26), a RhoG-specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and plays a role in promoting TWEAK-Fn14-mediated glioma invasion. Here, further investigation revealed an important role for SGEF in glioma cell survival. SGEF expression is upregulated by TWEAK-Fn14 signaling via NF-κB activity while shRNA-mediated reduction of SGEF expression sensitizes glioma cells to temozolomide-induced apoptosis and suppresses colony formation following temozolomide treatment. Nuclear SGEF is activated following temozolomide exposure and complexes with the DNA damage repair (DDR) protein BRCA1. Moreover, BRCA1 phosphorylation in response to temozolomide treatment is hindered by SGEF knockdown. The role of SGEF in promoting chemotherapeutic resistance highlights a heretofore unappreciated driver, and suggests its candidacy for development of novel targeted therapeutics for temozolomide-refractory, invasive GB cells., Implication: SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma., (©2016 American Association for Cancer Research.)

Published
2016
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2. The Src homology 3 domain-containing guanine nucleotide exchange factor is overexpressed in high-grade gliomas and promotes tumor necrosis factor-like weak inducer of apoptosis-fibroblast growth factor-inducible 14-induced cell migration and invasion via tumor necrosis factor receptor-associated factor 2.

Author

Fortin Ensign SP, Mathews IT, Eschbacher JM, Loftus JC, Symons MH, and Tran NL

Subjects
Blotting, Western, Cell Line, Tumor, Cell Movement drug effects, Cytokine TWEAK, Gene Expression Regulation, Neoplastic, Glioma metabolism, Glioma pathology, Guanine Nucleotide Exchange Factors metabolism, HEK293 Cells, Humans, Immunohistochemistry, Microscopy, Fluorescence, Neoplasm Invasiveness, Protein Binding drug effects, Pseudopodia genetics, Pseudopodia metabolism, RNA Interference, Receptors, Tumor Necrosis Factor metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Signal Transduction genetics, TNF Receptor-Associated Factor 2 metabolism, TWEAK Receptor, Tumor Necrosis Factors pharmacology, rac1 GTP-Binding Protein genetics, rac1 GTP-Binding Protein metabolism, rho GTP-Binding Proteins genetics, rho GTP-Binding Proteins metabolism, Cell Movement genetics, Glioma genetics, Guanine Nucleotide Exchange Factors genetics, Receptors, Tumor Necrosis Factor genetics, TNF Receptor-Associated Factor 2 genetics
Abstract

Glioblastoma (GB) is the highest grade of primary adult brain tumors, characterized by a poorly defined and highly invasive cell population. Importantly, these invading cells are attributed with having a decreased sensitivity to radiation and chemotherapy. TNF-like weak inducer of apoptosis (TWEAK)-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival and is dependent upon the activity of multiple Rho GTPases, including Rac1. Here we report that Src homology 3 domain-containing guanine nucleotide exchange factor (SGEF), a RhoG-specific guanine nucleotide exchange factor, is overexpressed in GB tumors and promotes TWEAK-Fn14-mediated glioma invasion. Importantly, levels of SGEF expression in GB tumors inversely correlate with patient survival. SGEF mRNA expression is increased in GB cells at the invasive rim relative to those in the tumor core, and knockdown of SGEF expression by shRNA decreases glioma cell migration in vitro and invasion ex vivo. Furthermore, we showed that, upon TWEAK stimulation, SGEF is recruited to the Fn14 cytoplasmic tail via TRAF2. Mutation of the Fn14-TRAF domain site or depletion of TNF receptor-associated factor 2 (TRAF2) expression by siRNA oligonucleotides blocked SGEF recruitment to Fn14 and inhibited SGEF activity and subsequent GB cell migration. We also showed that knockdown of either SGEF or RhoG diminished TWEAK activation of Rac1 and subsequent lamellipodia formation. Together, these results indicate that SGEF-RhoG is an important downstream regulator of TWEAK-Fn14-driven GB cell migration and invasion.

Published
2013
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