Cancer is a multi-step process that can progressively transform a healthy cell into a highly malignant one. The ability to evade apoptosis is a critical step in this transformation, an acquired capability that makes cancer cells impervious to endogenous and therapeutic cell death triggers. This hallmark of cancer makes it difficult to completely eliminate malignant cells from cancer patients. Despite its significance, however, the mechanisms that mediate this property of cancer cells remains poorly understood. The long-term goal of this project is to identify and understand the cellular pathways that allow otherwise healthy cells to become refractory to the endogenous death response. The overall objective of this application is to characterize novel death regulators that control apoptosis during development. Our central hypothesis is that critical components of the core apoptotic machinery are themselves controlled by genes of which we were previously unaware and that defects in these new regulators disrupt the ability to activate caspases. Our hypothesis has been formulated on the basis of preliminary data produced in our laboratory, having recently completed the first large-scale genetic screen of an endogenous death response in Drosophila. We have identified over twenty complementation groups in which tissues behave like they have acquired the ability to resist the death response. Importantly, most of these complementation groups map to genetic intervals without previously described regulators of cell death, indicating that we have identified a collection of entirely new regulators of programmed cell death. One of these complementation groups maps to a novel evolutionarily conserved gene we have named bulsa ("immortal" in Korean). We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following two specific aims: 1) Determine how mutations in bulsa confer resistance to cell death;and 2) Define a bulsa-specific pathway that controls the ability to activate caspases.
In aim 1 we will focus on bulsa as a prototypical death gene that can confer resistance to death triggers.
In aim 2 we will expand our study to include other candidate genes identified in our screen that act like bulsa and that together define a bulsa-specific pathway. These results are expected to have a positive impact, because the identified components will expand our understanding of the mechanisms that control apoptosis in new and unexpected directions.

Public Health Relevance

Current approaches to cancer therapy rely heavily on overpowering rapidly dividing malignant cells. Our approach is to better understand the mechanisms that allow cancer cells to evade cell death. The new knowledge gained from our efforts will provide a framework for developing rationally designed therapies to re- sensitize malignant cells to the death response, thereby increasing the efficacy of current cancer treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095944-03
Application #
8511727
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Maas, Stefan
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$268,357
Indirect Cost
$85,972
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kang, Yunsik; Bashirullah, Arash (2014) A steroid-controlled global switch in sensitivity to apoptosis during Drosophila development. Dev Biol 386:34-41
Ihry, Robert J; Bashirullah, Arash (2014) Genetic control of specificity to steroid-triggered responses in Drosophila. Genetics 196:767-80
Neuman, Sarah D; Ihry, Robert J; Gruetzmacher, Kelly M et al. (2014) INO80-dependent regression of ecdysone-induced transcriptional responses regulates developmental timing in Drosophila. Dev Biol 387:229-39