The goal of this program is to understand the function and regulation of nuclear oncogenes. Recent findings indicate that nuclear oncoproteins are the final targets and mediators of signal transduction pathways activated by growth factors and transforming oncoproteins that act in the cell surface or the cytoplasm. By modulating the expression and activity of nuclear oncoproteins, that act as sequence specific transcription factors, these agents affect the expression of genes involved in cell proliferation, migration, invasiveness and deposition of extracellular matrix. Much of this regulation occurs by changes in the phosphorylation level of nuclear oncoproteins. This program will focus on studying two transcription factors whose deregulated activation can lead to malignant transformation: AP-1 (jun/Fos) and E2A-Pbx1. While AP-1 is a primary regulator of genes involved in the control of cell proliferation, E2A- Pbx1 is likely to function by affecting the expression of other regulatory genes, such as jun and fos. To achieve its goals the program includes four projects that will investigate: 1) the function and regulation of the c-jun protooncogene; 2) the regulation of AP-1 activity by TGFbeta; 3) the mitogenic function of the vAb1 tyrosine kinase, and 4) the biochemical regulation and transforming mechanisms of E2A-Pbx1. A common theme shared by all of these projects is the investigation of how positively- and negatively-acting growth regulatory pathways affect the activities of nuclear oncoproteins by post-translational control mechanisms involving either protein phosphorylation or interactions with other proteins.
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