| Signal transduction is the process by which extracellular signals are transmitted to the inside of the cell where they affect cellular processes. These signals are integrated and transmitted by second messenger pathways, including lipid metabolism and kinase cascades. Mitogenic signals affect gene transcription and ultimately DNA replication and cell division. Therefore, mitogenic signals must affect nuclear processes. We hypothesize that just as plasma membrane lipid metabolism is involved in transmitting signals into the cytoplasm from the extracellular environment, lipid metabolism in the nuclear envelope is an active component in the transmission of signals from the cytoplasm to the nucleoplasm. We define this process as nuclear envelope signal transduction or NEST.;In this thesis I have examined the nuclear lipid metabolism induced by mitogens in fibroblasts. Growth factors cause an increase in diacylglycerol in the nuclear envelope. Molecular species analysis of the induced nuclear diacylglycerol and nuclear phospholipids demonstrates that in IIC9 cells responding to the growth factor $alpha$-thrombin, phosphatidylcholine is hydrolyzed in the nuclear envelope leading to the generation of diacylglycerol. This diacylglycerol mediates the translocation of protein kinase C to the nucleus. PKC then phosphorylates specific nuclear proteins.;I have further examined nuclear PC metabolism by developing a cell free system in which radiolabled PC is hydrolyzed by nuclear enzymes. Using this assay I have demonstrated a nuclear PC hydrolyzing PLA$sb2$ and PLD. While neither of these enzymes is likely to be responsible for nuclear PC-derived DAG, their products are involved in mitogenic signal transduction, and we hypothesize that the location of these lipid metabolism events in the nucleus is critical to their biological consequences. |
