Recent studies have demonstrated that tumor cells are more sensitive than normal cells to an apoptotic signal induced by a member of the tumor necrosis factor (TNF) family called TNF-related apoptosis- inducing ligand (TRAIL) also known as Apo2L. The applicant has made several interesting observations, including: (i) interferon gamma (INF- gamma) sensitizes A549, HT1090 and ME180 cancer cells to Apo2L-induced apoptosis; (ii) expression of transcription factor, INF regulatory factor (IFR-1), is also induced in these cells by INF-gamma; (iii) activation of Apo2L pathway activates specific caspases that induces cleavage of p120/Ras GTPase; and (iv) dexamethasone is a potent inhibitor of Apo2L-induced cell death. The goal of this application is to investigate the TRAIL/Apo2L pathway in tumor cells and define parts of the TRAIL/Apo2L signaling pathway that may lead to a better understanding the mechanisms underlying how cell killing of tumor cells occurs.
Three Specific Aims are proposed: (I) to examine the mechanisms by which IRF-1 regulates the sensitization of tumor cells by IFN-gamma to the Apo2L-induced apoptosis; (II) to characterize the role of caspase-mediated cleavage of ras GAP during Apo2L-induced apoptosis; and (III) to determine the targets of dexamethasone's actions in the Apo2L pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074275-03
Application #
6173269
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Mccarthy, Susan A
Project Start
1998-08-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2000
Total Cost
$202,135
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305