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J. Biol. Chem., Vol. 280, Issue 5, 3483-3492, February 4, 2005

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The Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK)-Fibroblast Growth Factor-inducible 14 (Fn14) Signaling System Regulates Glioma Cell Survival via NFB Pathway Activation and BCL-X_L/BCL-W Expression^*

Nhan L. Tran, Wendy S. McDonough, Benjamin A. Savitch, Thomas F. Sawyer, Jeffrey A. Winkles, and Michael E. Berens¶

From the Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004 and theDepartments of Surgery and Physiology and the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201

The Fn14 gene encodes a type Ia transmembrane protein that belongs to the tumor necrosis factor receptor superfamily. We recently showed that fibroblast growth factor-inducible 14 (Fn14) is overexpressed in migrating glioma cells in vitro and in glioblastoma multiforme clinical specimens in vivo. To determine the biological role of Fn14 in brain cancer progression, we examined the activity of Fn14 as a potential mediator of cell survival. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-stimulated glioma cells had increased cellular resistance to cytotoxic therapy-induced apoptosis. Either TWEAK treatment or Fn14 overexpression in glioma cells resulted in the activation of NFB and subsequently the translocation of NFB from the cytoplasm to the nucleus. In addition, Fn14 activation induced BCL-X_L and BCL-W mRNA and protein levels, and this effect was dependent upon NFB transcriptional activity. Substitution of a putative NFB binding site identified in the BCL-X promoter significantly decreased Fn14-induced transactivation. Furthermore Fn14-induced transactivation of the BCL-X promoter was also diminished by the super-repressor IB mutant, which specifically inhibits NFB activity, and by mutations in the NFB binding motif of the BCL-X promoter. Additionally small interfering RNA-mediated depletion of either BCL-X_L or BCL-W antagonized the TWEAK protective effect on glioma cells. Our results suggest that NFB-mediated up-regulation of BCL-X_L and BCL-W expression in glioma cells increases cellular resistance to cytotoxic therapy-induced apoptosis. We propose that the Fn14 protein functions, in part, through the NFB signaling pathway to up-regulate BCL-X_L and BCL-W expression to foster malignant glioblastoma cell survival. Targeted therapy against Fn14 as an adjuvant to surgery may improve management of invasive glioma cells and advance the outcome of this devastating cancer.

Received for publication, August 30, 2004 , and in revised form, November 8, 2004.

^* This work was supported by National Institutes of Health Grants NS-42262 (to N. L. T. and M. E. B.) and HL-39727 (to J. A. W.) and the Arizona State University School of Life Sciences undergraduate research fellowship (to B. A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: The Translational Genomics Research Institute, Neurogenomics Div., 445 North Fifth St., Phoenix, AZ 85004. Tel.: 602-343-8400; Fax: 602-343-8440; E-mail: mberens{at}tgen.org.

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