The main objectives of this grant proposal are: 1) The study of genes whose function is required for cell cycle progression in animal cells. In particular, we will concentrate on a) the regulation of expression of the Asparagine synthetase gene (AS) isolated by complementation of the ts11 G1 mutant of BHK cells. Expression of the AS gene is regulated by aminoacid starvation, both transcriptionally and post-transcriptionally. We wish to identify the cis and transacting elements involved in this regulation and the mechanism by which aminoacid deprivation leads to G1 arrest. b) The identification of the biochemical function of the BN51 gene, also isolated by complementation of a ts cell cycle mutant. 2) The study of the K-fgf oncogene, the growth factor it encodes and the FGF receptors. The K-fgf oncogene encodes a growth factor of the FGF family and transforms cells by creating an autocrine growth loop. We will investigate a) the regulation of expression of the K-fgf protooncogene and the restriction of its physiological expression to early stages of development. b) the physiological role of the K-FGF, using transgenic mice or gene-ablation techniques. c) the K-FGF domains involved in binding to low and high affinity FGF receptors. d) the interaction of K-FGF and other FGFs with their receptors, which also represent a gene family. e) the involvement of K-fgf in human neoplasias and the pathologies produced in mice by a recombinant K-fgf retrovirus which causes fibrosarcomas and hydrocephalus. Our main long range objective is the understanding of the regulation of normal and tumor cell proliferation. To this aim the study of the K-fgf oncogene and its growth factor should shed light on the mechanisms by which growth factors induce cell proliferation, and on the way this proliferative signal is regulated physiologically and pathologically. The studies of genes involved in cell cycle progression should provide complementary information on what regulates cell division from within.
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