The goal of this research is to use synchronized (G0/G1) human T-lymphocytes as a model system to determine the critical molecular events that regulate cell growth. We will use molecular genetic approaches to identify the ordered, sequential expression of genes and gene products that occurs during cell cycle progression. Particular emphasis will be placed upon cellular oncogene expression after activation of the T-cell antigen receptor complex vs. interleukin 2 receptors. Hybridization subtraction approaches will be used to clone previously unrecognized genes. The structure, cellular location and functional relevance of gene products will be determined using antibodies reactive with synthetic peptides and recombinant proteins. In addition, studies will be initiated to identify the relevance of other peptide hormones, especially insulin and insulin-like growth factors, that may function to facilitate movement through the cell cycle. The mechanism by which interleukin 2 influences the expression of high and low affinity interleukin 2 receptors, thereby regulating the potential responsiveness of proliferating T-cells, will be approached using IL-2 receptor cDNA transfectants and by studies of IL-2 receptor mRNA expression. The unique cellular and molecular reagents that will be applied to these studies, combined with our current knowledge of the determinants of T-cell cycle progression, promise to provide a model for cell growth that cannot be paralleled in existing eukaryotic cell culture systems. Consequently, forthcoming information should have immediate relevance, not only to the regulation of the T-cell immune response, but also to cell growth in general.
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