Interferons (IFN) are pleiotropic cytokines with diverse immune regulatory, anti-tumor, and anti-viral activities. Whereas several IFN-regulated genes with distinct anti- proliferative and anti-viral activities have been identified, many of the cellular mechanisms underlying these biologically- important effects of IFN remain unknown. Recently, we identified phospholipid scramblase-1 (PLSCR1) a plasma membrane protein implicated in Ca2+-dependent reorganization of plasma membrane phospholipids as a markedly IFN-upregulated gene. Our preliminary data also suggest that PLSCR1 itself exhibits anti- tumor and anti-viral activities that mimic effects normally associated with the response to IFN. In this proposal we aim to elucidate the specific role of IFN-regulated members of the PLSCR gene family in the overall biologic response to IFN.
Our Specific Aims i nclude: (1) to identify other members of the PLSCR gene family that may be regulated by IFN, and to identify cellular changes induced by IFN that are directly mediated by PLSCR1 or homologous proteins. Changes in topology of plasma membrane phospholipids in response to IFN will be evaluated and related to potential changes in the fatty acylation and intracellular distribution of newly synthesized PLSCR1 polypeptide. The possibility that PLSCR1 co-localizes with viral envelope proteins in detergent-resistant membrane """"""""rafts"""""""" will be explored, and the functional significance of conserved PPxY motifs common to PLSCR1 and many enveloped virus matrix and gag proteins will be determined; (2) to elucidate the specific contribution of PLSCR1 to IFN's anti-tumor activity. Tumor incidence in PLSCR1-null/p53-null mice will be determined and effects of IFN-alpha on the growth of PLSCR1-null and wild type tumors will be compared. Potential effects of PLSCR1 on cell proliferation and macrophage activation/recruitment will be examined; and (3) to determine the contribution of PLSCR1 to IFN's anti-viral activity. Vesicular stomatitis virus (VSV) replication in wild type and PLSCR1-null cells will be compared, both in presence and absence of IFN. Specific effects of cellular PLSCR1 on each stage of the viral life cycle will be identified. Potential anti-viral activity of PLSCR1 in vivo will be explored in wild type and PLSCR1-null mice. It is proposed that detailed understanding of the role of the PLSCR gene family in IFN biology may suggest novel anti-viral and anti-tumor strategies based on selective induction, activation, or mimicry of the PLSCR proteins.
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