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Controlling Cytoplasmic c-Fos Controls Tumor Growth in the Peripheral and Central Nervous System

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Abstract

Some 20 years ago c-Fos was identified as a member of the AP-1 family of inducible transcription factors (Angel and Karin in Biochim Biophys Acta 1072:129–157, 1991). More recently, an additional activity was described for this protein: it associates to the endoplasmic reticulum and activates the biosynthesis of phospholipids (Bussolino et al. in FASEB J 15:556–558, 2001), (Gil et al. in Mol Biol Cell 15:1881–1894, 2004), the quantitatively most important components of cellular membranes. This latter activity of c-Fos determines the rate of membrane genesis and consequently of growth in differentiating PC12 cells (Gil et al. in Mol Biol Cell 15:1881–1894, 2004). In addition, it has been shown that c-Fos is over-expressed both in PNS and CNS tumors (Silvestre et al. in PLoS One 5(3):e9544, 2010). Herein, it is shown that c-Fos-activated phospholipid synthesis is required to support membrane genesis during the exacerbated growth characteristic of brain tumor cells. Specifically blocking c-Fos-activated phospholipid synthesis significantly reduces proliferation of tumor cells in culture. Blocking c-Fos expression also prevents tumor progression in mice intra-cranially xeno-grafted human brain tumor cells. In NPcis mice, an animal model of the human disease Neurofibromatosis Type I (Cichowski and Jacks in Cell 104:593–604, 2001), animals spontaneously develop tumors of the PNS and the CNS, provided they express c-Fos (Silvestre et al. in PLoS One 5(3):e9544, 2010). Treatment of PNS tumors with an antisense oligonucleotide that specifically blocks c-Fos expression also blocks tumor growth in vivo. These results disclose cytoplasmic c-Fos as a new target for effectively controlling brain tumor growth.

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Acknowledgments

The authors wish to thank Karlyne M. Reilly, PhD from the NCI-Frederick (Frederick, MD, USA) for kindly providing the NPcis animals to establish our colony. This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica, FONCyT, the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Ministerio de, Ciencia y Tecnología de Argentina and SeCyt, Universidad Nacional de Córdoba, Argentina to BLC and PIDRI, Agencia Nacional de Promoción Científica y Tecnológica, FONCyT and Programa Raíces, (MinCyT) to GAG.

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The authors declare no conflict of interest.

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Author notes

  1. David C. Silvestre

    Present address: Institut Curie, Telomeres & Cancer Team - CNRS UMR 3244/UPMC, Bât. Trouillet-Rossignol, 2ème étage, 26 Rue d’Ulm, 75248, Paris, France

  2. Nicolás Tomasini

    Present address: Instituto de Patología Experimental, Facultad de Ciencias de la Salud, Universidad Nacional de Salta, 2 Piso, Avda. Bolivia 5150, 4400, Salta, Argentina

  3. Daniela F. Bussolino

    Present address: Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, 5000, Córdoba, Argentina

Authors and Affiliations

  1. Departamento de Química Biológica, CIQUIBIC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Pabellón Argentina, Ciudad Universitaria, 5000, Córdoba, Argentina

    Germán A. Gil, David C. Silvestre, Nicolás Tomasini, Daniela F. Bussolino & Beatriz L. Caputto

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  1. Germán A. Gil
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  2. David C. Silvestre
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  3. Nicolás Tomasini
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  4. Daniela F. Bussolino
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  5. Beatriz L. Caputto
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Correspondence to Beatriz L. Caputto.

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Special Issue: In Honor of Bob Leeden.

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Gil, G.A., Silvestre, D.C., Tomasini, N. et al. Controlling Cytoplasmic c-Fos Controls Tumor Growth in the Peripheral and Central Nervous System. Neurochem Res 37, 1364–1371 (2012). https://doi.org/10.1007/s11064-012-0763-8

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  • DOI: https://doi.org/10.1007/s11064-012-0763-8

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