The experiments proposed in this application are designed to elucidate the mechanism(s) by which TGF beta 1 binding transduces a growth stimulatory or growth inhibitory signal. While many investigators utilize TGF beta 1 or TGF beta 1-like molecules, little is known about the mechanism through which the TGF beta 1 signal is transduced to the cell nucleus. Our recent data, however, indicate that a guanine nucleotide regulatory protein (G protein) is coupled to TGF beta 1 binding in mesenchymal and epithelial cells. A model is proposed suggesting that TGF beta 1 affects cellular regulation by at least two distinct mechanisms, one is G protein-independent and the other is G protein-dependent. The G protein-independent pathway is coupled to TGF beta 1-stimulated extracellular matrix/cytoskeletal gene expression while the G protein-dependent pathway regulates soft agar growth and expression of the proto-oncogenes c-sis, c-fos, and c-myc. We wish to expand upon these results and determine the nature of the G protein coupled to the TGF beta 1 receptor(s). This will be accomplished by the following specific aims: 1). determine whether a G protein is coupled to TGF beta 1 binding in transformed cell lines or epithelial cells growth inhibited by TGF beta 1; 2). isolate nontransformed epithelial cell variants refractile to TGF beta 1 growth inhibition with altered or abrogated TGF beta 1/G protein coupling; and 3). purification of the specific G protein coupled to TGF beta 1 binding. A mixture of biochemical, genetic, and molecular approaches are utilized in these studies. Information concerning the mechanism of TGF beta 1 action in normal cellular proliferation and transformation should result.
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