During the previous years of this project, the applicant has found that TGF-alpha transfection of early malignant colon carcinoma cells results in the acquisition of growth factor independence (GFI) with increased tumorigenicity in athymic nude mice. Similarly, anti-sense TGF-alpha expression in late malignant colon cancer cells decreases tumorigenicity and induces the re-acquisition of growth factor dependence (GFD). GFI appears to be related to aberrant expression of TGF-alpha in non-dividing growth states where it is normally downregulated. This aberrant TGF-alpha expression in late malignant cells depends upon dysregulation of transcriptional control. The cis-element of the TGF-alpha promotor mediating dysregulation has been identified and characterized. In addition, the applicant has demonstrated that aberrant expression of TGF-alpha allowed for continued EGF receptor (EGFR) activation in non-dividing states. Thus, the applicant now wants to characterize the transcription factors necessary for autostimulatory regulation of the TGF-alpha promotor dysregulative cells. Gel shift analyses suggest that downregulation of trans-acting factors that bind with the cis-element for TGF-alpha autoregulation occurs in quiescent GFD cells, while GFI cells show constitutive expression of these factors in growth arrested states. In GFD cells, insulin-like growth factor I (IGF-I) stimulates EGFR and entry into S phase. Therefore, the applicant proposes to study how IGF-I-R acts as a cofactor for entry into DNA synthesis. Thus, the specific aims of this application are, first, to characterize the TGF-alpha autoregulatory transcription factors. The second specific aim is to determine the mechanistic basis for the downregulation of TGF-alpha autocrine activity in GFD cells and its dysregulation in GFI cells. The final specific aim is to determine the effects of autocrine TGF-alpha dysregulation on the control of cell cycle transit.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034432-15
Application #
6149988
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Freeman, Colette S
Project Start
1982-02-01
Project End
2002-01-31
Budget Start
2000-02-28
Budget End
2001-01-31
Support Year
15
Fiscal Year
2000
Total Cost
$267,583
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Surgery
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Leiphrakpam, Premila D; Agarwal, Ekta; Mathiesen, Michelle et al. (2014) In vivo analysis of insulin-like growth factor type 1 receptor humanized monoclonal antibody MK-0646 and small molecule kinase inhibitor OSI-906 in colorectal cancer. Oncol Rep 31:87-94
Leiphrakpam, Premila D; Rajput, Ashwani; Mathiesen, Michelle et al. (2014) Ezrin expression and cell survival regulation in colorectal cancer. Cell Signal 26:868-79
Agarwal, Ekta; Chaudhuri, Anathbandhu; Leiphrakpam, Premila D et al. (2014) Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer. BMC Cancer 14:145
Zou, Yi; Howell, Gillian M; Humphrey, Lisa E et al. (2013) Ron knockdown and Ron monoclonal antibody IMC-RON8 sensitize pancreatic cancer to histone deacetylase inhibitors (HDACi). PLoS One 8:e69992
Chowdhury, Sanjib; Ongchin, Melanie; Sharratt, Elizabeth et al. (2013) Intra-tumoral heterogeneity in metastatic potential and survival signaling between iso-clonal HCT116 and HCT116b human colon carcinoma cell lines. PLoS One 8:e60299
Agarwal, Ekta; Brattain, Michael G; Chowdhury, Sanjib (2013) Cell survival and metastasis regulation by Akt signaling in colorectal cancer. Cell Signal 25:1711-9
Wang, Jing; Rajput, Ashwani; Kan, Julie L C et al. (2009) Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma. J Biol Chem 284:10912-22
Sawhney, Rajinder S; Liu, Wensheng; Brattain, Michael G (2009) A novel role of ERK5 in integrin-mediated cell adhesion and motility in cancer cells via Fak signaling. J Cell Physiol 219:152-61
Li, Fengzhi; Brattain, Michael G (2006) Role of the Survivin gene in pathophysiology. Am J Pathol 169:1-11