c-Fos-activated synthesis of nuclear Phosphatidyl Inositol-4,5-bisphosphate (PtdIns(4,5)P2) promotes global transcriptional changes.?

GABRIEL ORLANDO FERRERO; MARIANE RENNER; GIL GERMAN ALEJANDRO; LUCIA RODRÍGUEZ-BERDINI ; BEATRIZ LEONOR CAPUTTO

Bari

Congreso; 54th International Conference on the Bioscience of Lipids (ICBL): Linking Transcription to Physiology in Lipidomics; 2013

ICBL

The oncoprotein c-Fos is a well-recognized member of the AP-1 family of transcription factors. In addition to this canonical activity, we have previously shown that cytoplasmic c-Fos activates phospholipid synthesis through a mechanism independent of its genomic AP-1 activity. c-Fos associates with particular enzymes of the pathway of synthesis of lipids at the endoplasmic reticulum and increases the Vmax of the reactions without modifying the Km values. This lipid synthesis activation is found associated to events of differentiation and proliferation that require high rates of membrane biogenesis. Since lipid synthesis has been shown to occur also 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. Using in vitro and in culture studies, we show that nuclear-localized c-Fos associates with and activates PI4P5K thus promoting PtdIns(4,5)P2 formation. This increased formation of PtdIns(4,5)P2 in its turn, promotes transcriptional changes. We propose c-Fos as a key regulator of nuclear PtdInsPs synthesis in response to growth signals that results in c-Fos-dependent transcriptional changes promoted by the newly synthesized lipids.