Ionizing Radiation (IR) induces p53-dependent and p53-independent apoptosis. Understanding p53-dependent apoptosis has benefited immensely from studies in mammalian cells that identified biochemical activities and genetic analysis in model organisms such as C. elegans and Drosophila that identified genes responsible for the activities. In contrast, IR- induced p53-independent apoptosis lacked a genetic model and remains poorly understood at the molecular level. Studies in recent funding period indicate that in the absence of any p53-like activity, made possible by mutations in the sole p53 family member in Drosophila, irradiated cells undergo robust apoptosis, thus providing the first genetic model to study IR-induced p53- independent apoptosis. p53-dependent and p53-independent apoptosis in Drosophila share common features such as the requirement for caspase activity and exacerbation by impaired DNA damage checkpoints or DNA repair. The key difference between p53-dependent apoptosis and p53-independent apoptosis is that net E2F activity appears to promote the former but inhibit the latter. To understand p53-independent apoptosis at the molecular level, a combination of genetic and cytological approaches will be used to identify and study genes and their products needed for this mode of cell death in Drosophila. The use of IR to eradicate tumors relies on its ability to induce cell death. Although p53- dependent apoptosis remains most widely studied, it is p53-independent apoptosis that is crucial for eliminating p53-deficient tumors, which constitute the majority of solid tumors. Experiments proposed will lead to a better understanding of p53-independent apoptosis in vivo in a multi-cellular context. Given the conservation of gene function between Drosophila and human, research proposed here has the potential to help us maximize the efficacy of radiation therapy of human cancers.

Public Health Relevance

The use of ionizing radiation to eradicate tumors relies on its ability to induce cell death. Although p53-dependent apoptosis remains most widely studied, it is p53-independent apoptosis that is crucial for eliminating p53-deficient tumors, which constitute the majority. Experiments proposed here will lead to a better understanding of p53- independent apoptosis that results from radiation exposure in a Drosophila model. Because of excellent conservation of gene function between Drosophila and human, what we learn may allow us to maximize the efficacy of radiation therapy of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087276-04
Application #
8327206
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Maas, Stefan
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$307,931
Indirect Cost
$102,110
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Bilak, Amber; Uyetake, Lyle; Su, Tin Tin (2014) Dying cells protect survivors from radiation-induced cell death in Drosophila. PLoS Genet 10:e1004220
Su, Tin Tin (2011) Safeguarding genetic information in Drosophila. Chromosoma 120:547-55
Edwards, Anthony; Gladstone, Mara; Yoon, Petros et al. (2011) Combinatorial effect of maytansinol and radiation in Drosophila and human cancer cells. Dis Model Mech 4:496-503
Gladstone, Mara; Su, Tin Tin (2011) Screening for radiation sensitizers of Drosophila checkpoint mutants. Methods Mol Biol 782:105-17
Gladstone, Mara; Su, Tin Tin (2011) Chemical genetics and drug screening in Drosophila cancer models. J Genet Genomics 38:497-504
Wichmann, Anita; Uyetake, Lyle; Su, Tin Tin (2010) E2F1 and E2F2 have opposite effects on radiation-induced p53-independent apoptosis in Drosophila. Dev Biol 346:80-9