c-Fos-activated synthesis of nuclear phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] promotes global transcriptional changes

c-Fos is a well-recognized member of the AP-1 (activator protein-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 lipid synthesis pathway at the endoplasmic reticulum and increases the V max of the reactions without modifying the K m values. This lipid synthesis activation is associated with 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, in the present study 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 PI4P5K (phosphatidylinositol-4-monophosphate 5-kinase), but not with PI4KIIIβ (type IIIβ phosphatidylinositol 4-kinase) thus promoting PtdIns(4,5) P 2 (phosphatidylinositol 4,5-bisphosphate) formation, which, in turn, promotes transcriptional changes. We propose c-Fos as a key regulator of nuclear PtdIns(4,5) P 2 synthesis in response to growth signals that results in c-Fos-dependent transcriptional changes promoted by the newly synthesized lipids. Abbreviations: Angptl4, angiopoietin-like 4; Anxa8, annexin A8; AP-1, activator protein-1; BAF, Brg/Brm-associated factor; BASP1, brain-abundant membrane-attached signal protein 1; CaXII, carbonic anhydrase 12; ER, endoplasmic reticulum; Fn1, fibronectin 1; IP, immunoprecipitation; Klf4, Kruppel-like factor 4; Mmp3, matrix metallopeptidase 3; NM, nuclear matrix; NP40, Nonidet P40; NSB, Nuclei Storage Buffer; Pdgfra, platelet-derived growth factor receptor α; PI4KIII, type III phosphatidylinositol 4-kinase; PI4P5K, phosphatidylinositol 4-monophosphate 5-kinase; Prkcc, protein kinase Cγ; PtdInsP, polyphosphoinositide; PtdIns(4)P, phosphatidylinositol 4-monophosphate; PtdIns(4,5)P2, phosphatidylinositol 4,5-bisphosphate; PtdIns(5)P, phosphatidylinositol 5-monophosphate; PtdSer, phosphatidylserine; Ptn, pleiotrophin; qPCR, quantitative real-time PCR; RT–PCR, reverse transcription–PCR