In the previous period of support for this project we characterized an intracellular TGFalpha autocrine loop. Cells with an intracellular TGFalpha express high amounts of intracellular precursor TGFalpha which has an abnormally slow rate of processing relative to other cells. Consequently, they continue to express high intracellular levels of TGFalpha in non-dividing, non-cycling states such as the quiescent state generated by nutrient and growth factor deprivation. The intracellular location of the autocrine activity results in the inaccessibility of TGFalpha autocrine activity in these cells to TGFalpha neutralizing antibodies and EGFtau blocking antibodies. However, constitutive TGFalpha anti-sense vector expression results in the acquisition of EGF dependency. Anti-sense transfected cells do not express high levels of intracellular TGFalpha and show decreased TGFalpha expression and transcription in non- dividing states. They are similar to well-differentiated, growth factor dependent colon carcinoma cells in this regard as these cells also require exogenous EGF for clonal growth and release from quiescence. They also show low levels of intracellular TGFalpha and reduced expression of TGFalpha in non-dividing states. These results have led us to hypothesize that TGFalpha acts as an autocrine factor to aid in the initiation of clonal growth or the escape from quiescence in colon carcinoma cells and that its internal location in some cells provides a growth regulatory advantage due to inappropriately high expression in non-cycling growth states such as quiescence. It is further hypothesized that the factor does not have a stimulatory function for exponentially growing cells. Moreover, it has recently been found that other EGF related peptides, amphiregulin (AR), and cripto (CR), are also autocrine regulatory factors in colon cancer. We hypothesize that these factors will interrelate with TGFalpha in terms of control of expression and temporal control of function. These hypothesizes will be tested by: 1. Determining the autocrine function of TGFalpha in exponential and non- dividing growth regulatory states. 2. Determine interrelationship of control of expression among TGFalpha, AR and CR. 3. Determine the autocrine function of AR. 4. Determine the autocrine function of CR.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA054807-08S1
Application #
6033504
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Spalholz, Barbara A
Project Start
1991-08-01
Project End
1999-12-31
Budget Start
1999-06-01
Budget End
1999-12-31
Support Year
8
Fiscal Year
1999
Total Cost
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; Brattain, Michael G; Black, Jennifer D et al. (2018) TGF? and IGF1R signaling activates protein kinase A through differential regulation of ezrin phosphorylation in colon cancer cells. J Biol Chem 293:8242-8254
Contreras, Jacob I; Robb, Caroline M; King, Hannah M et al. (2018) Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy. ACS Chem Biol 13:1148-1152
Robb, Caroline M; Kour, Smit; Contreras, Jacob I et al. (2018) Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy. Oncotarget 9:5216-5232
Bailey, Katie L; Agarwal, Ekta; Chowdhury, Sanjib et al. (2017) TGF?/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells. PLoS One 12:e0176096
Robb, Caroline M; Contreras, Jacob I; Kour, Smit et al. (2017) Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). Chem Commun (Camb) 53:7577-7580
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Fisher, Kurt W; Das, Binita; Kim, Hyun Seok et al. (2015) AMPK Promotes Aberrant PGC1? Expression To Support Human Colon Tumor Cell Survival. Mol Cell Biol 35:3866-79
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

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