Basic fibroblast growth factor (bFGF) is a potent angiogenesis factor and mediator of vascular cell function. A unique property of bFGF is that multiple forms are translated from a single mRNA via the use of separate initiation codons. These bFGF forms have distinct subcellular distributions. The smallest (18 kD) form is predominantly cytosolic; the high molecular weight (HMW) forms show a strong nuclear localization. In addition these forms induce different phenotypes. NIH 3T3 cells producing 18 kD bFGF display the properties of transformed cells, i.e. increased motility, increased growth, decreased bFGF receptor number, and increased surface beta1 integrins. Cells producing high levels of HMW bFGF also grow to high saturation densities, like 18 kD bFGF transformed cells, but show no increase in motility or beta1 surface integrins and no receptor down-regulation. In addition, HMW bFGF transformants grow in 1% serum, whereas 18 kDa bFGF transformants do not. Properties associated with 18 kD bFGF transformants are reverted by coexpression of a dominant negative FGF receptor, but those of HMW bFGF transformants are not. Curiously, cells expressing only moderate levels of HWM bFGF are growth inhibited. These results suggest that HMW bFGF utilizes a different mechanism for transformation than 18 kD bFGF, a mechanism that separates growth from certain other membrane events, and that this mechanism is, perhaps, related to its unique subcellular localization. In this grant we propose to test this hypothesis. First, the process of nuclear localization will be analyzed by examining the metabolic requirements, such as temperature and time dependence, saturability, reversibility, and pathway for nuclear import in in vitro and in vivo systems. The structural requirements for nuclear localization will be dissected using mutated forms of bFGF as well as peptides representing the amino terminus. Second, the mechanism of transformation by over-expression of HMW bFGF will be characterized. This will include a molecular analysis of the structural requirements for HMW bFGF-mediated transformation, characterization of proteins that associate with HMW bFGF, and characterization of two nuclear phosphotryosine-containing proteins whose abundance correlates with the HMW bFGF transformed state. Third, the mechanism for growth inhibition by moderate expression of HMW bFGF will be analyzed. This will include characterization of cells whose growth is inhibited by HMW bFGF, the analysis of the structural requirements for growth inhibition, and the development of genetic systems for the elucidation of growth control by HMW bFGF
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