Transforming Growth Factor beta (TGFbeta) induces extra cellular matrix (ECM) remodeling, inhibits cellular proliferation and suppresses malignant behavior. TGFbeta, however, has also been reported to stimulate malignant behavior. It is not clear how ECM remodeling is integrated into the TGFbeta function. The Principal Investigator has unified several hypotheses to integrate ECM remodeling, through intergin activation at focal adhesion contacts, with the tumor-suppression pathway of E-cadherin activation or the tumor-promoting pathway of beta- catenin activation. The long term objective of this application is to determine how ECM remodeling is integrated into the function of TGFbeta. The proposed hypotheses and specific aims are: Hypothesis I: TGFbeta-induced ECM remodeling activates integrin-dependent signaling at focal adhesion contacts and links with the antiproliferative and tumor-suppressive pathways of E-cadherin activation.
Specific Aim 1 : Determine how ECM remodeling and integrin signaling leads to the induction of E-Cadherin by TGFbeta; investigate the functional significance of E-cadherin in the antiproliferative and tumor-suppressive action of TGFbeta. Hypothesis II: TGFbeta-induced beta-catenin, if undegradated, is an underlying mechanism by which TGFbeta stimulates malignant cell behavior.
Specific Aim 2 : Determine how beta-catenin is activated and the functional significance of beta-catenin induction and its complex formation with adenomatous polyposis coli (APC) to bring about tumor-suppressive behavior.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA047775-18
Application #
7124503
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Ault, Grace S
Project Start
1988-08-01
Project End
2007-11-30
Budget Start
2005-07-01
Budget End
2007-11-30
Support Year
18
Fiscal Year
2005
Total Cost
$158,960
Indirect Cost
Name
Southern Illinois University School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038415006
City
Springfield
State
IL
Country
United States
Zip Code
62794
Liu, Guangming; Hu, Xin; Varani, James et al. (2009) Calcium and calcium sensing receptor modulates the expression of thymidylate synthase, NAD(P)H:quinone oxidoreductase 1 and survivin in human colon carcinoma cells: promotion of cytotoxic response to mitomycin C and fluorouracil. Mol Carcinog 48:202-211
Wang, Hongmei; Promkan, Moltira; Liu, Guangming et al. (2008) Switch of transforming growth factor beta function from tumor suppression to stimulation in adenomatous polyposis coli (APC) knocked-down human colon carcinoma cells. Cancer Lett 272:253-9
Wang, Huijun; Rajan, Shanthi; Liu, Guangming et al. (2008) Transforming growth factor beta suppresses beta-catenin/Wnt signaling and stimulates an adhesion response in human colon carcinoma cells in a Smad4/DPC4 independent manner. Cancer Lett 264:281-7
Wang, Hongmei; Radjendirane, Venugopal; Wary, Kishore K et al. (2004) Transforming growth factor beta regulates cell-cell adhesion through extracellular matrix remodeling and activation of focal adhesion kinase in human colon carcinoma Moser cells. Oncogene 23:5558-61
Chakrabarty, S; Liu, B R; Rajagopal, S (2001) Disruption of transforming growth factor beta-regulated laminin receptor function by expression of antisense laminin, a chain RNA in human colon cancer cells. J Cell Physiol 186:47-52
Wang, H; Chakrabarty, S (2001) Requirement of protein kinase Calpha, extracellular matrix remodeling, and cell-matrix interaction for transforming growth factorbeta-regulated expression of E-cadherin and catenins. J Cell Physiol 187:188-95
Rajagopal, S; Moskal, T L; Wang, H et al. (1999) Efficacy and specificity of antisense laminin chain-specific expression vectors in blocking laminin induction by TGFbeta1: effect of laminin blockade on TGFbeta1-mediated cellular responses. J Cell Physiol 178:296-303
Fan, D; Chakrabarty, S; Seid, C et al. (1989) Clonal stimulation or inhibition of human colon carcinomas and human renal carcinomas mediated by transforming growth factor-beta 1. Cancer Commun 1:117-25