title: Controlling cytoplasmic c-Fos controls tumor growth in the peripheral and central nervous system.
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.
authors.affiliation: Departamento de Química Biológica, CIQUIBIC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Pabellón Argentina, Ciudad Universitaria, 5000 Córdoba, Argentina.
authors.forename: Germán A
authors.initials: GA
authors.lastname: Gil
authors.forename: David C
authors.initials: DC
authors.lastname: Silvestre
authors.forename: Nicolás
authors.initials: N
authors.lastname: Tomasini
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Bussolino
authors.forename: Beatriz L
authors.initials: BL
authors.lastname: Caputto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002490:Central Nervous System / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D016716:PC12 Cells; D010524:Peripheral Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology*; D010743:Phospholipids / Q000096:biosynthesis*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats
chemical_list: D016376:Oligonucleotides, Antisense; D010743:Phospholipids; D016760:Proto-Oncogene Proteins c-fos