PHOSPHOLIPID SYNTHESIS ACTIVATION BY c-FOS. IMPLICATIONS IN BRAIN TUMOR CELL PROLIFERATION

PRUCCA CG; VELAZQUEZ FN; CARDOZO- GIZZI AM; CAPUTTO, BL

Buenos Aires

Congreso; XLIX Reunion Anual Sociedad Argentina de Investigación en Bioquímica y Biología.; 2013

c-Fos belongs to the AP-1 family of transcription factors. Our laboratory determined that in addition to this AP-1 activity, c-Fos associates to the endoplasmic reticulum (ER) and activates the synthesis of phospholipids, the main components of cell membranes. We previously observed that c-Fos is over-expressed in brain tumors in contrast with non-pathological tissues where c- Fos is rarely detected. We established a correlation between the malignancy of brain tumors and the % colocalization of c-Fos with the ER markers. The aim of this study is to design and test putative negative dominant mutants of c-Fos that can block its action as an activator of phospholipid synthesis. The domain NA of c-Fos (aa 1-138) associates to the ER but does not activate phospholipids synthesis, acting as negative dominant mutant. To facilitate the future therapeutic application of mutants, we are seeking for the smallest truncated forms of NA that retain dominant negative capacity. We found that NA deletion mutants diminish tumor cell proliferation whereas FRET-FLIM microscopy shows that the presence of NA reduces c-Fos interaction with PI4KIIα, a key enzyme of phospholipid metabolism. NA domain of c-Fos and its truncated forms show promising features to be used as dominant negative peptides to block the action of c-Fos in malignant brain tissues.