Regulation of Cell Phospholipid Metabolism by Phospholipase A2

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The regulation of glycerophospholipid metabolism is fundamental to cell homeostasis as these molecules have important roles in both membrane structure and cell signaling. Recent studies indicate that the 80 kDa calcium-independent phospholipase A2 (iPLA2) plays a fundamental role in the regulation of phospholipid metabolism. This study is intended to further elucidate the mechanisms of regulation of the expression and catalytic activity of this essential enzyme. Experiments are designed to determine if iPLA2 activity is regulated by the accumulation of truncated forms of the protein that are encoded by alternatively spliced iPLA2 messages. These studies will focus on the cell cycle dependence of iPLA2 activity, as this is likely to have important implications for the accumulation of phospholipid mass for daughter cell membranes and potentially for the regulation of cell cycle progression. Among the studies to be performed are the quantification of full length and splice variant mRNAs and proteins at each phase of the cell cycle and the over expression of the splice variants to determine if this reduces the catalytic activity of endogenous iPLA2. Other experiments are focused on the potential regulation of iPLA2 expression by Sterol Response Element Binding Proteins (SREBP) and sterol metabolism. Several recent reports suggest that glycerophospholipid and sterol metabolism are coordinately regulated and preliminary experiments suggest that iPLA2 expression may be modulated by changes in sterol mass. To address this question, a putative Sterol Response Element (SRE) in the iPLA2 promoter will be characterized. In addition, experiments will be performed to determine if iPLA2 expression is induced in cells with low sterol content and if this is can be attributed to SREBP. Together these studies should provide important insights into the regulation of iPLA2 in mammalian cells. Given the essential role that iPLA2 plays in glycerophospholipid metabolism, these studies should provide information that is fundamental to our understanding of cell homeostasis. Cell membranes are largely composed of lipid molecules that until recently were thought to play a simple structural role in cell physiology. However, recent studies indicate that lipids have information content and can be broken down into other molecules that can regulate cell behavior. This research is intended to further our understanding of a critical enzyme, iPLA2, which regulates a subclass of lipids, the phospholipid molecules. As this enzyme controls the phospholipid content of cell membranes, it can have dramatic effects on both the integrity of a cell and its ability to respond to changes in its environment. These studies are designed to further elucidate mechanisms controlling both the amount of iPLA2 in cells (expression) and the functioning of the enzyme (activity). Together, these studies should provide insights into the regulation of an enzyme that plays a critical role in phospholipid metabolism. Given the importance of these molecules in controlling cell integrity and responsiveness, this information will be crucial to further our knowledge of how cells function.