Neurochemical Research

, Volume 37, Issue 6, pp 1364–1371 | Cite as

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

  • Germán A. Gil
  • David C. Silvestre
  • Nicolás Tomasini
  • Daniela F. Bussolino
  • Beatriz L. Caputto
Original Paper

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.

Keywords

Cytoplasmic c-Fos Brain tumors Membrane biogenesis Phospholipid synthesis Regulation 

Supplementary material

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Supplementary material 1 (TIFF 1787 kb)
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Supplementary material 3 (TIFF 1794 kb)

References

  1. 1.
    Angel P, Karin M (1991) The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation. Biochim Biophys Acta 1072:129–157PubMedGoogle Scholar
  2. 2.
    Morgan JI, Curran T (1995) Immediate early genes: ten years on. Trends Neurosci 18:66–67PubMedCrossRefGoogle Scholar
  3. 3.
    Caputto BL, Guido ME (2000) Immediate early gene expression within the visual system: light and circadian regulation in the retina and the suprachiasmatic nucleus. Neurochem Res 25:153–162PubMedCrossRefGoogle Scholar
  4. 4.
    Kouzarides T, Ziff E (1989) Leucine zippers of fos, jun and GCN4 dictate dimerization specificity and thereby control DNA binding. Nature 340:568–571PubMedCrossRefGoogle Scholar
  5. 5.
    Shaulian E, Karin N (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4(5):E131–E136PubMedCrossRefGoogle Scholar
  6. 6.
    Guido ME, de Arriba Zerpa GA, Bussolino DF, Caputto BL (1996) Immediate early gene c-fos regulates the synthesis of phospholipids but not of gangliosides. J Neurosci Res 43:93–98PubMedCrossRefGoogle Scholar
  7. 7.
    Bussolino DF, de Arriba Zerpa GA, Grabois VR, Conde CB, Guido ME, Caputto BL (1998) Light affects c-fos expression and phospholipid synthesis in both retinal ganglion cells and photoreceptor cells in an opposite way for each cell type. Brain Res Mol Brain Res 58:10–15PubMedCrossRefGoogle Scholar
  8. 8.
    Bussolino DF, Guido ME, Gil GA, Borioli G, Renner ML, Grabois VR, Conde CB, Caputto BL (2001) c-Fos associates with the endoplasmic reticulum and activates phospholipid metabolism. FASEB J 15:556–558. doi:10.1096/fj00-0446fje PubMedGoogle Scholar
  9. 9.
    Cobellis G, Meccariello R, Fienga G, Pierantoni R, Fasano S (2002) Cytoplasmic and nuclear Fos protein forms regulate resumption of spermatogenesis in the frog, Rana esculenta. Endocrinology 143:163–170PubMedCrossRefGoogle Scholar
  10. 10.
    Gil GA, Bussolino DF, Portal MM, Alfonso Pecchio A, Renner ML, Borioli GA, Guido ME, Caputto BL (2004) c-Fos activated phospholipid synthesis is required for neurite elongation in differentiating PC12 cells. Mol Biol Cell 15:1881–1894PubMedCrossRefGoogle Scholar
  11. 11.
    Silvestre DC, Gil GA, Tomasini N, Bussolino DF, Caputto BL (2010) Growth of peripheral and central nervous system tumors is supported by cytoplasmic c-Fos in humans and mice. PLoS ONE 5(3):e9544PubMedCrossRefGoogle Scholar
  12. 12.
    de Arriba Zerpa GA, Guido ME, Bussolino DF, Pasquaré SJ, Castagnet PI, Giusto NM, Caputto BL (1999) Light exposure activates retina ganglion cell lysophosphatidic acid acyl transferase and phosphatidic acid phosphatase by a c-Fos-dependent mechanism. J Neurochem 73:1228–1235PubMedCrossRefGoogle Scholar
  13. 13.
    Alfonso Pecchio AR, Cardozo Gizzi AO, Renner ML, Molina-Cavalita M, Caputto BL (2011) c-Fos activates and physically interacts with specific enzymes of the pathway of synthesis of polyphosphoinositides. Mol Biol Cell 22:4716–4725PubMedCrossRefGoogle Scholar
  14. 14.
    Crespo PM, Silvestre DC, Gil GA, Maccioni HJ, Daniotti JL, Caputto BL (2008) c-Fos activates glucosylceramide synthase and glycolipid synthesis in PC12 cells. J Biol Chem 283:31163–31171PubMedCrossRefGoogle Scholar
  15. 15.
    Guido ME, Caputto BL (1990) Labeling of retina and optic tectum phospholipids in chickens exposed to light or dark. J Neurochem 55:1855–1860PubMedCrossRefGoogle Scholar
  16. 16.
    Torgerson TR, Colosia A, Donahue P, Yao-Zhong L, Hawiger J (1998) Regulation of NF-Kβ, AP-1, N-FAR and STAT1 nuclear import in T lymphocytes by noninvasive delivery of peptide carrying the nuclear localization sequence of NF-Kβ p50. J Immunol 161:6084–6092PubMedGoogle Scholar
  17. 17.
    Teicher BA, Menon K, Alvarez E, Galbreath E, Shih C, Faul M (2001) Antiangiogenic and antitumor effects of a protein kinase C beta inhibitor in human T98G glioblastoma multiforme xenografts. Clin Cancer Res 7:634–640PubMedGoogle Scholar
  18. 18.
    Portal MM, Ferrero GO, Caputto BL (2007) N-Terminal c-Fos tyrosine phosphorylation regulates c-Fos/ER association and c-Fos-dependent phospholipid synthesis activation. Oncogene 26:3551–3558PubMedCrossRefGoogle Scholar
  19. 19.
    Ferrero GO, Velazquez FN, Caputto BL (2011) The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity. Oncogene. doi:10.1038/onc.2011.510
  20. 20.
    Silvestre DC, Maccioni HJ, Caputto BL (2009) Content of endoplasmic reticulum and Golgi complex membranes positively correlates with the proliferative status of brain cells. J Neurosci Res 87:857–865PubMedCrossRefGoogle Scholar
  21. 21.
    Cichowski K, Jacks K (2001) NF1 tumor suppressor gene function: narrowing the GAP. Cell 104:593–604PubMedCrossRefGoogle Scholar
  22. 22.
    Rasmussen SA, Yang Q, Friedman JM (2001) Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet 68:1110–1118PubMedCrossRefGoogle Scholar
  23. 23.
    Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T (2000) Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26:109–113PubMedCrossRefGoogle Scholar
  24. 24.
    Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME, Bronson RT, Jacks T (1999) Mouse models of tumor development in neurofibromatosis type 1. Science 286:2172–2176PubMedCrossRefGoogle Scholar
  25. 25.
    Costa RM, Silva AJ (2003) Mouse models of neurofibromatosis type I: bridging the GAP. Trends Mol Med 9:19–23PubMedCrossRefGoogle Scholar
  26. 26.
    Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, Magdaleno S, Dalton J, Calabrese C, Board J, Macdonald T, Rutka J, Guha A, Gajjar A, Curran T, Gilbertson RJ (2005) Radial stem cells are candidate stem cells of ependymoma. Cancer Cell 8:323–335PubMedCrossRefGoogle Scholar
  27. 27.
    Zhu Y, Parada LF (2002) The molecular and genetic basis of neurological tumours. Nature Rev Cancer 2:616–626CrossRefGoogle Scholar
  28. 28.
    Morgan JI, Cohen DR, Hempstead JL, Curran T (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237:192–196PubMedCrossRefGoogle Scholar
  29. 29.
    Gleave ME, Monia BP (2005) Antisense therapy for cancer. Nature 5:468–479Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Germán A. Gil
    • 1
  • David C. Silvestre
    • 1
    • 2
  • Nicolás Tomasini
    • 1
    • 3
  • Daniela F. Bussolino
    • 1
    • 4
  • Beatriz L. Caputto
    • 1
  1. 1.Departamento de Química Biológica, CIQUIBIC, Facultad de Ciencias QuímicasUniversidad Nacional de CórdobaCórdobaArgentina
  2. 2.Institut Curie, Telomeres & Cancer Team - CNRS UMR 3244/UPMC, Bât. Trouillet-RossignolParisFrance
  3. 3.Instituto de Patología Experimental, Facultad de Ciencias de la SaludUniversidad Nacional de SaltaSaltaArgentina
  4. 4.Departamento de Farmacología, Facultad de Ciencias QuímicasUniversidad Nacional de CórdobaCórdobaArgentina

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