HETEROCHROMATIN RECRUITMENT OF THE VPAC1 LOCUS BY IKAROS

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DESCRIPTION (provided by applicant): The focus of this proposal is to investigate the molecular mechanisms governing Ikaros-mediated transcriptional regulation of vasoactive intestinal peptide receptor - 1 (VPACR-1) in T lymphocytes. Ikaros is a master regulator of lymphopoiesis and sets the threshold for T cell activation. Ikaros mutated mouse models develop an aggressive lymphoblastic leukemia with 100% incidence. Some human leukemias express mutated dominant negative Ikaros isoforms that inhibit full-length Ikaros DNA binding. Decreases in Ikaros DNA binding capacity may downregulate a subset of genes capable of regulating T cell proliferation. Recently, we demonstrated that the gene for VPACR-1, a G protein coupled, antiproliferative receptor expressed on na¿ve CD4 T cells, is a novel gene target for Ikaros. Signaling through the anti-proliferative VPACR-1 receptor may naturally impede cell cycle entry in CD4 T cells. Therefore, a decrease in Ikaros protein and/or DNA binding capacity, during certain etiologies of lymphoblastic leukemia, may downregulate VPACR-1 and contribute to uncontrolled proliferation. Understanding how Ikaros regulates VPACR-1 in na¿ve and activated CD4T cells may 1.) provide insight into a crucial downstream event from Ikaros that contributes to uncontrolled proliferation in hematopoietic disorders and 2.) lead to an understanding of the role Ikaros-mediated regulation of VPACR-1 plays in normal immune function, such as suppressing bystander T cell activation in certain organs including the gastrointestinal system. Therefore, the aims of this research are to 1.) confirm bi-directional effects of Ikaros on VPACR-1 expression in primary na¿ve and activated CD4 T lymphocytes, 2.) demonstrate which PKC pathway signaling proteins mediate TCR-dependent VPACR-1 downregulation, and 3.) identify IK phosphoacceptor residues that mediate IK recruitment to heterochromatin during T cell activation