Date of Award

Spring 1-1-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Leslie Leinwand

Second Advisor

Tin Tin Su

Third Advisor

James DeGregori

Fourth Advisor

Brian DeDecker

Fifth Advisor

Rui Yi

Abstract

Life or death choices of cells in Drosophila depend on the accumulation of critical levels of pro-apoptotic factors such as hid. Ionizing radiation (IR) causes lesions to macromolecules in cells that trigger damage responses and result in death of cells expressing critical amounts of hid. Cells are eliminated by apoptosis to prevent the transfer of damaged genetic material to daughter cells. However, some cells must be preserved in order for organisms to survive and regenerate. Therefore, genes that limit apoptosis can enhance organismal survival. The ban miRNA limits apoptosis after IR exposure by regulating the 3'UTR of hid. Though important for developmental apoptosis and proliferation, ban is also activated by radiation-induced apoptosis, and promotes organismal and cellular survival after IR exposure. To better understand how pro- and anti-apoptotic factors regulate survival after IR exposure I screened for genes that could modify ban function in a dose-dependent manner. I identified Tie, a receptor tyrosine kinase in the VGFR/PDGFR family, as an important regulator of IR-induced increases in ban activity and levels. Previously, the only known role for Tie in Drosophila was in long-range signaling in border cell migration. Although tie is not required for development, it is required for radiation survival. These suggest that tie instructs ban activity in radiation responses. Additionally, tie is required for protection from radiation-induced apoptosis conferred by death of neighboring cells.

Although many questions remain to be answered, this work provides a further level of insight into how life and death decisions of cells are regulated following exposure to IR. Since IR is used in cancer therapies to induce apoptosis, I hope that this work could contribute to development of more effective cancer therapies.

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