c-Fos-activated Synthesis of Nuclear Phosphatidyl Inositol-4,5-bisphosphate [PtdIns(4,5)P2] Promotes Global Transcriptional Changes

GABRIEL FERRERO; RENNER ML; GIL GERMAN; RODRIGUEZ LUCIA; CAPUTTO BL

BIOCHEMICAL JOURNAL

PORTLAND PRESS LTD

Lugar: Londres; Año: 2014 vol. 1 p. 233 - 244

0264-6021

c-Fos is a well-recognized member of the AP-1 family of transcription factors. In addition to this canonical activity, we previously showed 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 associated to events of differentiation and proliferation that require high rates of membrane biogenesis. Since lipid synthesis also occurs in the nucleus, and different phospholipids have been assigned transcription regulatory functions, herein we examine if c-Fos also acts as a regulator of phospholipid synthesis in the nucleus. Furthermore, we examine if c-Fos modulates transcription through its phospholipid synthesis activator capacity. We show that nuclear-localized c-Fos associates with and activates Phosphatidyl Inositol 4 monophosphate 5 Kinase [PI4P5K] but not with Type III Beta Phosphatidyl Inositol 4 Kinase [PI4KIIIβ] thus promoting Phosphatidyl Inositol-4,5-bisphosphate [PtdIns(4,5)P2] formation which, in its turn, promotes transcriptional changes. We propose c-Fos as a key regulator of nuclear PtdIns(4,5)P2 synthesis in response to growth signals that results in c-Fos-dependent transcriptional changes promoted by the newly synthesized lipids. Summary statement: c-Fos promotes transcriptional changes by activating Phosphatidyl Inositol-4,5-bisphosphate synthesis in the nucleus. Regulatory transcriptional functions of c-Fos can now be extended to its phospholipid synthesis activator capacity, which means that new mechanisms of transcriptional regulation can be envisaged