Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
2R35CA042568-08
Application #
3479441
Study Section
Special Emphasis Panel (SRC (88))
Project Start
1986-06-01
Project End
2000-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012

  Publications

Schwenger, P; Alpert, D; Skolnik, E Y et al. (1998) Activation of p38 mitogen-activated protein kinase by sodium salicylate leads to inhibition of tumor necrosis factor-induced IkappaB alpha phosphorylation and degradation. Mol Cell Biol 18:78-84
Bellosta, P; Zhang, Q; Goff, S P et al. (1997) Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation. Oncogene 15:2387-97
Costa, M; Bellosta, P; Basilico, C (1996) Cleavage and release of a soluble form of the receptor tyrosine kinase ARK in vitro and in vivo. J Cell Physiol 168:737-44
Li, Y; Basilico, C; Mansukhani, A (1994) Cell transformation by fibroblast growth factors can be suppressed by truncated fibroblast growth factor receptors. Mol Cell Biol 14:7660-9
Rappolee, D A; Basilico, C; Patel, Y et al. (1994) Expression and function of FGF-4 in peri-implantation development in mouse embryos. Development 120:2259-69
Guerrini, L; Gong, S S; Mangasarian, K et al. (1993) Cis- and trans-acting elements involved in amino acid regulation of asparagine synthetase gene expression. Mol Cell Biol 13:3202-12
Bellosta, P; Talarico, D; Rogers, D et al. (1993) Cleavage of K-FGF produces a truncated molecule with increased biological activity and receptor binding affinity. J Cell Biol 121:705-13
Ittmann, M; Ali, J; Greco, A et al. (1993) The gene complementing a temperature-sensitive cell cycle mutant of BHK cells is the human homologue of the yeast RPC53 gene, which encodes a subunit of RNA polymerase C (III). Cell Growth Differ 4:503-11
Talarico, D; Ittmann, M M; Bronson, R et al. (1993) A retrovirus carrying the K-fgf oncogene induces diffuse meningeal tumors and soft-tissue fibrosarcomas. Mol Cell Biol 13:1998-2010
Chaudhuri, M M; Moscatelli, D; Basilico, C (1993) Involvement of the conserved acidic amino acid domain of FGF receptor 1 in ligand-receptor interaction. J Cell Physiol 157:209-16

Showing the most recent 10 out of 29 publications