The long-term objective of this grant application is to elucidate the control of cellular proliferation and how transformation arises. Cellular proliferation is regulated, in large part, by growth factor modulated G1 events.
The Specific Aims of this proposal will investigate the mechanisms by which growth factors regulate the stimulation of the mitogenic process and traverse of the G1 phase of the cell cycle. Because platelet-derived growth factor (PDGF) initiates proliferation of fibroblasts, the PDGF inducible gene products will be identified and their role in growth regulation determined. The investigators will employ standard biochemical and cellular experimental methods to purify PDGF inducible proteins. Antibodies to PDGF inducible proteins will be developed and exploited. In order to investigate the transfer of the mitogenic signal from receptor to nucleus and changes in gene expression, the mechanism whereby PDGF alters the expression of an inducible gene will be investigated. The molecular process involved in the putative negative control of PDGF inducible genes will be explored with both the DNA binding site and the binding protein being characterized. This gene system will be used to develop an in vitro transcription system to explore the mitogen stimulated cellular events that bring about changes in gene expression. The role of somatomedin C/insulin like growth factor (SmC/IGF-I) in the traverse of cells through G1 will be investigated. The biochemical and cellular events controlled by SmC/IGF-I will be studied. This will include mainly post-transcription events such as modification of proteins and SmC/IGF-I modulation of translational mechanisms. The investigations proposed in this application will be conducted mainly in non-transformed fibroblasts. However, it is the intent to examine and compare all growth controlling events that we discover in non-transformed cells with transformed cells. The understanding of the control of the mammalian cell cycle and the regulation of gene expression will allow the exploration of the transformation processes. Control phenomena in fibroblastic cells will also be examined in other cell types. The information we obtain can lead to better diagnostics and treatments for numerous clinical situations.
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