Ataxia telangiectasia (AT) is a complex, multisystemic human genetic disease with particular significance to the radiation biologist because of its extreme cellular radiation sensitivity. Although there has been considerable investigation into possible mechanisms for this sensitivity, and gene cloning and mapping have been aggressively pursued, the gene(s) responsible for the AT defect has not yet been identified. In this proposal, we employ a strategy using AT as a model system exhibiting a low background of radiation resistance to study genes that may affect radiation sensitivity and may be AT complementing, or downstream of the AT locus. We have used vector-mediated gene transfer with a cDNA expression library that contains Epstein Barr virus (EBV) oriP sequences and a selectable marker to transform radiation-sensitive AT5BIVA cells. By selection with large fractions of ionizing radiation, we have isolated a clone of transformed AT cells expressing """"""""wild-type"""""""" fibroblast radiation sensitivity (ATCL2-11). Plasmid rescue and polymerase chain reaction amplifications permitted the identification of seven candidate cDNAs present in these transformed cells. In the performance of experiments proposed in this grant, we will identify and characterize the gene(s) responsible for modifying the radiation sensitivity of AT cells. The results of these investigations should provide insight into molecular factors affecting radiation sensitivity, and possible, into the nature of the AT cellular defect responsible for the acute radiation sensitivity of AT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA063023-05
Application #
2633871
Study Section
Special Emphasis Panel (ZRG7-SSS-1 (07))
Program Officer
Pelroy, Richard
Project Start
1994-01-15
Project End
1998-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Georgetown University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Lee, S A; Dritschilo, A; Jung, M (2001) Role of ATM in oxidative stress-mediated c-Jun phosphorylation in response to ionizing radiation and CdCl2. J Biol Chem 276:11783-90
Varghese, S; Schmidt-Ullrich, R K; Dritschilo, A et al. (1999) Enhanced radiation late effects and cellular radiation sensitivity in an ATM heterozygous breast cancer patient. Radiat Oncol Investig 7:231-7
Varghese, S; Jung, M (1998) Overexpression of Rb and E2F-1 in ataxia-telangiectasia lymphocytes. Arch Pharm Res 21:640-4
Lee, S A; Dritschilo, A; Jung, M (1998) Impaired ionizing radiation-induced activation of a nuclear signal essential for phosphorylation of c-Jun by dually phosphorylated c-Jun amino-terminal kinases in ataxia telangiectasia fibroblasts. J Biol Chem 273:32889-94
Lee, S J; Dimtchev, A; Lavin, M F et al. (1998) A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB. Oncogene 17:1821-6
Jung, M; Zhang, Y; Dimtchev, A et al. (1998) Impaired regulation of nuclear factor-kappaB results in apoptosis induced by gamma radiation. Radiat Res 149:596-601
Jung, M; Zhang, Y; Dritschilo, A (1997) Expression of a dominant negative I kappa B-alpha modulates hypersensitivity of ataxia telangiectasia fibroblasts to streptonigrin-induced apoptosis. Radiat Oncol Investig 5:265-8
Jung, M; Lee, S A; Zhang, Y et al. (1997) Regulation of p53 in response to ionizing radiation in ataxia telangiectasia fibroblasts. Int J Radiat Oncol Biol Phys 37:417-22
Jung, M; Kondratyev, A; Lee, S A et al. (1997) ATM gene product phosphorylates I kappa B-alpha. Cancer Res 57:24-7
Jung, M; Zhang, Y; Lee, S et al. (1995) Correction of radiation sensitivity in ataxia telangiectasia cells by a truncated I kappa B-alpha. Science 268:1619-21

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