The overall objective of these studies is to elucidate the role of polypeptide growth factors in the genesis of both epithelial and mesenchymal neoplasms. Previous studies from this laboratory have demonstrated that (1) transforming growth factor, type Beta (TGFBeta) is a ubiquitous growth regulatory molecule; (2) specific cell membrane receptor for TGFBeta are present on a wide variety of cell types; (3) TGFBeta can either be growth stimulatory or growth inhibitory wih the response obtained depending largely on cell type; (4) certain chemically transformed mesenchymal cells both produce and respond in a proliferative manner to TGFBeta; and (5) transformed keratinocytes may lose their normally inhibitory response to TGFBeta. The proposed studies are designed to test the hypothesis that alterations in production of and/or response to TGFBeta may play a role in neoplastic transformation. Transformation could result from either an increased stimulatory response in many connective tissue neoplasms or a decreased inhibitory response in epithelial and certain other neoplasms. These hypotheses will be tested and the mechanism of TGFBeta growth stimulation of certain cell types and growth inhibition of other cell types will be investigated through the following specific aims: (2) a determination of the nature of the active TGFBeta precursor and the physiological mechanism of activation. This is likely to be an important regulatory step in TGFBeta action since most cells tested both produce TGFBeta in an inactive form and have TGFBeta membrane receptors. (2) A determination of whether the TGFBeta mRNA content varies with growth or transformation state by using the cDNA probe for mouse TGFBeta. (3) A determination of the genes controlling responsiveness to TGFBeta by examining known growth related genes constitutively expressed in resting chemically transformed cells relative to resting nontransformed cells. We have previously shown that a major change in the chemically transformed cells is an increased responsiveness to TGFBeta, a function that is apparently modulated in part through expression of the c-myc gene. (4) A comparison of genes induced by TGFBeta in cells stimulated and inhibited by TGFBeta in an attempt to understand the mechanisms whereby a pure factor can act as a growth stimulator for one cell type and a growth inhibitor for another. (5) A comparison of the inhibitory response to TGFBeta in human mammary epithelial cells and related neoplastically transformed cells and a determination of the mechanism of loss of the inhibitory response.
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