The induction of p53 and apoptosis in response to ionizing radiation and other stressors in vivo varies greatly between normal tissues, between cell types within a tissue, and between tumor types. Our long-term goal is to understand the basis of this tissue specificity. One approach is to analyze the tissue specificity of the p53 response pathway in genetic mutants of putative upstream regulators of p53, notably the P13K family members DNAPK and Atm. These analyses have shown that in response to gamma radiation (1) DNAPK is not required to upregulate p53 or apoptosis. In fact, mutation in DNAPK sensitizes cells, even p53 null cells, to apoptosis. This demonstrates a novel DNAPK dependent anti-apoptotic pathway. (2) Atm is required to upregulate p53 and apoptosis in some tissue, but is not required in all tissues such as epithelium indicating there are compensatory pathways to regulate p53 and apoptosis and the relative importance of these compensatory pathways varies between tissue types. (3) DNAPK and Atm functionally collaborate in that simultaneous mutation in both genes results in synthetic lethality early in embryogenesis. We propose to (1) determine if mutation in DNAPK can also radiosensitize p53 null tumor cells and to characterize this novel DNAPK dependent anti-apoptotic pathway, (2) determine if DNAPK, Atm and Atr are redundant in regulating p53 and apoptosis in vivo, (3) determine the morphologic and cellular basis of lethality of DNAPK Atm compound mutant embryos, and if altered regulation of p53 or apoptosis contributes to this defect. Understanding the functional interaction of the P13 Ks, in regulating p53, apoptosis, development and carcinogenesis at the level of the whole animal is a necessary link to apply knowledge gained from cell culture models to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070414-09
Application #
6858676
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Pelroy, Richard
Project Start
1996-05-10
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
9
Fiscal Year
2005
Total Cost
$384,925
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Gurley, Kay E; Ashley, Amanda K; Moser, Russell D et al. (2017) Synergy between Prkdc and Trp53 regulates stem cell proliferation and GI-ARS after irradiation. Cell Death Differ 24:1853-1860
Moser, Russell; Toyoshima, Masafumi; Robinson, Kristin et al. (2012) MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency. Mol Cancer Res 10:535-45
Busch, Stephanie E; Gurley, Kay E; Moser, Russell D et al. (2012) ARF suppresses hepatic vascular neoplasia in a carcinogen-exposed murine model. J Pathol 227:298-305
Grosse-Wilde, Anne; Voloshanenko, Oksana; Bailey, S Lawrence et al. (2008) TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. J Clin Invest 118:100-10
Grosse-Wilde, Anne; Kemp, Christopher J (2008) Metastasis suppressor function of tumor necrosis factor-related apoptosis-inducing ligand-R in mice: implications for TRAIL-based therapy in humans? Cancer Res 68:6035-7
Bailey, S Lawrence; Gurley, Kay E; Hoon-Kim, Kyung et al. (2008) Tumor suppression by p53 in the absence of Atm. Mol Cancer Res 6:1185-92
Gurley, Kay E; Kemp, Christopher J (2007) Ataxia-telangiectasia mutated is not required for p53 induction and apoptosis in irradiated epithelial tissues. Mol Cancer Res 5:1312-8
Kemp, Christopher J (2005) Multistep skin cancer in mice as a model to study the evolution of cancer cells. Semin Cancer Biol 15:460-73
Philipp-Staheli, Jeannette; Kim, Kyung-Hoon; Liggitt, Denny et al. (2004) Distinct roles for p53, p27Kip1, and p21Cip1 during tumor development. Oncogene 23:905-13
Gurley, K E; Vo, K; Kemp, C J (1998) DNA double-strand breaks, p53, and apoptosis during lymphomagenesis in scid/scid mice. Cancer Res 58:3111-5

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