Radio-resistance is a major cause of treatment failure in patients with overwise localized, curable malignancies. Ras transfection of rodent cells offers a useful model system to study aspects of the radio-resistant phenotype since it allows the reliable creation of radio-resistant cells on a uniform genetic background. This system permits experiments to determine how signal transduction through the ras oncogene is affecting radio-sensitivity by altering the cell cycle response of transferred cells to radiation causing a prolongation of the radiation induced G2 delay. This application will examine three aspects of the ras associated phenotype. It will examine the relationship of radio-resistance and the G2 delay to ras expression. We will block ras action and determine the effect on radiation survival and cell cycle perturbations. It will begin to dissect which of the ras signal transduction pathways is involved in the induction of radio-resistance. We will utilize ras effector domain mutants, mutant members of signal transduction pathways which interact with ras and inhibitors of signal transduction components to identify the key signal transduction elements which are necessary for expression of the ras associated phenotypes. Finally, we will examine how ra expression effects known effectors of the G2 transition, including cyclin B, cdc2 and cdc25C. These studies should enable us to develop a mechanistic model for the induction of radiation resistance by activated oncogene expression. In addition, portions of these aims rely on interactions with other members of the group to specifically address the role of KILLER/DR5 and ATM in radio-resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA075138-03S1
Application #
6323310
Study Section
Project Start
2000-06-01
Project End
2001-05-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$140,673
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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