Phospholipid scramblase 1 (PLSCR1) is one of a family of four conserved Ca -binding, multiply-palmitoylated, endofacial plasma membrane proteins thought to contribute to the transbilayer movement of phosphatidylserine and other membrane phospholipids following cell injury and apoptosis. We recently discovered that expression of PLSCR1 is transcriptionally induced by several cytokines, including growth factors known to regulate cellular proliferation and maturation, and such increase in cellular PLSCR1 appears required for normal proliferation and terminal differentiation of myeloid precursors into granulocytes or macrophages. A component of this newly synthesized PLSCR1 localizes within the nucleus, and nuclear import of PLSCR1 was found to occur whenever the polypeptide failed to palmitoylate, as required for its membrane retention. We also recently showed that nuclear import of PLSCR1 is actively mediated by the importin-nucleopore transport system, reflecting an unconventional nuclear localization signal identified in the protein. By contrast, palmitoylated PLSCR1 is a component of plasma membrane lipid """"""""rafts"""""""", membrane microdomains believed to be involved in both assembly of receptor signaling platforms and endocytic trafficking of activated receptors from the plasma membrane. In this application, we focus on the function of nuclear PL scramblase in blood and other cells, with the overall goal of determining how induction of the expression of PLSCR1 and its importinalpha/beta-mediated transport into the nucleus impacts upon the expression of other genes potentially involved in regulating proliferative, maturational and apoptotic responses of leukocytes and other blood cells to growth factors and related cytokines.
Specific Aims i nclude (1) to deduce the structure of the PLSCRI/importin-alpha complex and to identify key residues controlling their interaction;(2) to identify target DNA sequence of nuclear PLSCR1 and potential binding motifs with gene regulatory function;(3) to identify the DMA-binding domain in PLSCR1;&(4) to identify those genes whose transcription is regulated by nuclear PLSCR1 and to determine the functional consequence of resulting change in cellular expression of their gene products.
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