Regulatory gene hierarchies underlying the development of B and T cells from a presumptive lymphoid precursor are at present poorly defined. The Oct-2 gene encodes a developmental regulator of immunoglobulin gene transcription, and is likely to represent a member of a regulatory gene hierarchy responsible for B cell differentiation. The Oct-2 protein is a member of the POU box family of regulators and is a tissue specific transcription factor. Transient ectopic expression of Oct-2 in HeLa cell results in the activation of a co-transfected immunoglobulin promoter construct. In myeloma x fibroblast cell hybrids extinction of immunoglobulin gene expression correlates with loss of Oct-2 expression. The expression of Oct-2 is not exclusively restricted to cells of the B lineage. Oct-2 is expressed in some transformed T cell lines. We have found that the Oct-2 gene is expressed at low levels in resting T cell clones and the gene is up-regulated upon T cell activation by signalling through the T cell receptor. To date, no function for Oct-2 has been demonstrated in cells of the T lineage. The goal of this project is to investigate the function and regulation of Oct-2 during the development and maturation of T lymphocytes.
The specific aims are to: 1) analyze the expression of Oct-2 during T cell development and functional maturation; 2) dissect the regulatory mechanism controlling Oct-2 expression during T cell activation including the characterization of regulatory elements in the Oct-2 gene that enable expression in T cells and responsiveness to external stimuli; 3) identify T cell target genes for Oct-2 by testing regulatory regions of cloned genes as well as by attempting to clone DNA segments which are specifically photochemically cross-linked with Oct-2 in vivo; 4)test the function of Oct-2 during T cell activation by blocking expression or' function with the use of anti-sense CDNA constructs or dominant negative Oct-2 mutants, respectively. This project will not only complement ongoing studies on Oct-2 in B lymphocytes, but will provide an excellent system for examining how a common tissue specific transcription factor functions in the regulatory networks of two distinct, but related cell lineages. Such an analysis will provide insight into molecular mechanisms controlling the normal and malignant development of lymphocytes.
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