PROTO-ONCOGENES AND CELLULAR PROLIFERATION

Project: Research project

Project Details

Description

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.
StatusNot started

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