c-Fos, a Novel Target to Control Tumor Development in Neurofibromatosis Type 1

NICOLÁS TOMASINI; DAVID C. SILVESTRE; BEATRIZ L. CAPUTTO

Valle Hermoso, Córdoba

Workshop; Tango Lessons for Brain Cancer Research: Understanding Cellular Intricacy, Improvising New Therapies; 2007

James McDonnell Foundation

c-Fos is a member of the family of AP-1 transcription factors. It heterodimmerizes with c-Jun and regulates the expression of genes involved in mitosis and differentiation. We found that c-Fos, in addition to its transcription factor activity, associates to the endoplasmic reticulum (ER) and activates the synthesis of phospholipids for the genesis of membrane required for cell growth. Herein, c-Fos activated phospholipid synthesis was examined in brain and peripheral tumors (neurofibromas) occurring spontaneously in B6 mice heterocigotes for the p53 and Nf1 genes (NPcis mice), an animal model for the Neurofibromatosis Type 1 (NF1) disease. High Leveles of c-Fos were observed co-localizing with ER markers both in brain tumors and neurofibromas. These levels correspond with high rates of cell proliferation. NPcis mice were treated intracranially with antisensene oligonucleotide (ASO) for c-Fos mRNA and sacrificed 28 days later. Brain specimens were examined for rates of phospholipid synthesis and expression of the cell proliferation marker PCNA. It was found that in brain regions subjected to ASO treatment, phospholipid synthesis rates were lower than those of the conunterpart non-treated contra-lateral hemisphere. In addition, ASO abolished PCNA expression. By contrast, AP-1 content as determined by EMSA was not affected. These results support the importance of cytoplasmic c-Fos in supporting normal and exacerbated growth of cells derived from the nervous system and may be a therapeutical target for controlling tumor growth in NF1.