Cell proliferation in higher eukaryotes is a tightly regulated process that is largely governed by extracellular factors. These include hormones, growth factors, growth inhibitors and the cellular microenvironment, for example, the proximity of neighboring cells. Tumorigenic cells exhibit faulty or unregulated growth control, and they often fail to heed one or more of the environmental signals that limit the proliferation of normal cells. There is substantial evidence that growth-controlling environment signals have acute effects upon the expression of specific genes that are though important for the proliferative response. This proposal examines the biochemical mechanisms by which environmental signals alter the expression of certain genes in nontumorigenic murine fibroblasts, in tumorigenic derivatives derived by chemical or viral transformation, and in transfected derivatives bearing one or more known genetic change. The experiments will determine the intracellular pathways by which some environmental factors induce or suppress the transcription, mRNA accumulation or translation of certain growth-related genes, the role of certain protein kinases and other regulatory proteins in mediating changes in gene expression and the proliferative response, and they will explore the function of some of the genes in regulating proliferation. These studies will provide an important biochemical and molecular biological base for understanding the interactions between environmental signals and specific gene expression in the regulation of normal and tumor cell growth.
