Growth and apoptosis responses of B-lymphocytes determine the nature of the B lymphocyte repertoire during B cell development and the nature of the immune response in the periphery. Egr-1 is an immediate early gene shown to be induced by B cell receptor (BCR) triggering in mature B cells but its induction in immature B cells is much reduced. Mature but not immature B cells proliferate to BCR cross-linking. Egr-1 is a Zinc finger containing transcription factor that is widely expressed and is linked to cell growth and differentiation responses. It has been shown to be also important for growth response of fibroblasts, endothelial cells, smooth muscle cells, T cells, prostrate cancer cells and is constitutively expressed in many lymphomas. Down regulation of Egr-1 results in growth inhibition in several B lymphoma cells. This proposal will use a g cell lymphoma model as well as normal immature and mature B cells to define the early signaling events that affect Eg-1 expression leading to growth and apoptosis responses in B cells. It is based on our observation that expression of Egr-1 is differentially regulated in mature and immature B cells and that down regulation of Egr-1 mRNA and protein is intimately related to apoptosis response of BKS-2, a B lymphoma with an immature phenotype. Our specific aims are: 1. To determine if expression of human Egr-1 can overcome growth inhibition in antisense Egr-1 treated lymphoma cells and to determine if Egr-1 levels affect apoptosis or growth responses of mature B cells. 2. To determine if Egr-1 expression in BKS-2 cells is regulated at the level of transcription and to define the regions of Egr-1gene promoter that are important for its down regulation in BKS-2 cells. 3. To define the upstream signaling events that are distinct between BKS-2 cells, immature and mature B cells that lead to differential regulation of Egr-1 expression. 4. To determine the importance of NF-AT pathway for Egr-1 downregulation in BKS-2 cells. 5. To determine the in vivo role of Egr-1 in B cell development and to study the role of egr-1 in lymphoma development using transgenic mice expressing a dominant negative Egr-1 protein. These studies are likely to be important for understanding of normal B cell development as well as growth regulation of normal and transformed B cells.