c-FOS-ACTIVATED SYNTHESIS OF NUCLEAR PTDINS(4,5)P2 PROMOTES GLOBAL TRANSCRIPTIONAL CHANGES

FERRERO, GO; RENNER, ML; GIL, GA; RODRÍGUEZ, L; CAPUTTO, BL

Buenos Aires

Congreso; Molecular mechanisms in cell signaling and gene expression - Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2013

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

In addition to the canonical activity of c-Fos as a transcription factor, we previously showed that cytoplasmic c-Fos activates phospholipid synthesis by an AP-1independent mechanism. For this, c-Fos associates with particular enzymes of the pathway of synthesis of lipids at the endoplasmic reticulum. Since lipid synthesis has been shown to occur in the nucleus, and different phospholipids have been assigned transcription regulatory functions, herein we examine if c-Fos acts as a regulator of phospholipid synthesis also in the nucleus. We also examine if c- Fos is able to modulate transcription through its phospholipid synthesis activator capacity. In vitro and in culture studies showed nuclear-localized c-Fos associated with and activating Phosphatidyl Inositol-4-phosphate 5 Kinase, but not Type III β Phosphatidyl Inositol 4 Kinase, thus promoting Phosphatidyl Inositol-4,5-bisphosphate [PtdIns(4,5)P2] formation. c-Fos-promoted increased PtdIns(4,5)P2 formation promotes AP-1-independent transcriptional changes. The regulatory transcriptional functions of c-Fos can now be extended to its capacity to activate phospholipid synthesis. We propose c-Fos as a key regulator of nuclear polyphosphoinositide synthesis in response to growth signals and hypothesize that both c-Fos-AP-1 independent and c-Fos-AP-1 dependent mechanisms will work coordinately when a cell re-enters the cell cycle.