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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA042572-03
Application #
3479454
Study Section
(SRC)
Project Start
1986-07-01
Project End
1993-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
Forrester, Elizabeth; Chytil, Anna; Bierie, Brian et al. (2005) Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res 65:2296-302
Bhowmick, Neil A; Ghiassi, Mayshan; Aakre, Mary et al. (2003) TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. Proc Natl Acad Sci U S A 100:15548-53
Law, Brian K; Chytil, Anna; Dumont, Nancy et al. (2002) Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol Cell Biol 22:8184-98
Bhowmick, N A; Zent, R; Ghiassi, M et al. (2001) Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. J Biol Chem 276:46707-13
Satterwhite, D J; White, R L; Aakre, M E et al. (2001) TGF-beta1 regulates the expression of multiple max-interacting transcription factors in Balb/MK cells: implications for understanding the mechanism of action of TGF-beta1. Pediatr Res 50:67-75
Entingh, A J; Law, B K; Moses, H L (2001) Induction of the C/EBP homologous protein (CHOP) by amino acid deprivation requires insulin-like growth factor I, phosphatidylinositol 3-kinase, and mammalian target of rapamycin signaling. Endocrinology 142:221-8
McDonnell, M A; Law, B K; Serra, R et al. (2001) Antagonistic effects of TGFbeta1 and BMP-6 on skin keratinocyte differentiation. Exp Cell Res 263:265-73
Bragg, A D; Moses, H L; Serra, R (2001) Signaling to the epithelium is not sufficient to mediate all of the effects of transforming growth factor beta and bone morphogenetic protein 4 on murine embryonic lung development. Mech Dev 109:13-26
Law, B K; Norgaard, P; Moses, H L (2000) Farnesyltransferase inhibitor induces rapid growth arrest and blocks p70s6k activation by multiple stimuli. J Biol Chem 275:10796-801
Datta, P K; Moses, H L (2000) STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling. Mol Cell Biol 20:3157-67

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