proposal): This proposal is aimed at defining the molecular mechanisms by which the steroid hormone ecdysone regulates programmed cell death in Drosophila. The larval midgut and salivary glands undergo massive stage-specific apoptosis in response to two sequential pulses of ecdysone during metamorphosis. Entry of these tissues into programmed cell death is foreshadowed by the induction of two key death inducer genes, reaper and hid. The goal of this proposal is to identify the ecdysone-inducible transcription factors that directly regulate stage-specific reaper and hid expression. It has been shown that the ecdysone-inducible transcription factors encoded by the Broad-Complex and E74 are required for salivary gland cell death as well as reaper and hid transcription. It will be determined whether this is a direct regulatory link. It will also be determined whether the Broad-Complex and E74 play a similar role in the earlier induction of reaper and hid in doomed larval midguts. The hypothesis that stage-specific Rel/NF-kB and AP-1 signaling converge with the steroid signal to determine the appropriate temporal regulation of cell death will be tested. Finally, the minimal sequences in the reaper and hid promoters that are required for proper hormone-induced stage-specific transcription will be identified and these sequences will be used to identify other factors that contribute to this regulation. This proposal provides a means of understanding the molecular mechanisms by which nuclear receptors, NF-kB and AP-1 converge to direct a programmed cell death response. In addition, this study will provide insight into the molecular mechanisms by which systemic hormonal signals are refined into stage- and tissue-specific biological responses during development.
| Mahoney Jr, William M; Hong, Jeong-Ho; Yaffe, Michael B et al. (2005) The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members. Biochem J 388:217-25 |
| Yin, Viravuth P; Thummel, Carl S (2004) A balance between the diap1 death inhibitor and reaper and hid death inducers controls steroid-triggered cell death in Drosophila. Proc Natl Acad Sci U S A 101:8022-7 |
| Ward, Robert E; Reid, Pamela; Bashirullah, Arash et al. (2003) GFP in living animals reveals dynamic developmental responses to ecdysone during Drosophila metamorphosis. Dev Biol 256:389-402 |
| Lehmann, M; Jiang, C; Ip, Y T et al. (2002) AP-1, but not NF-kappa B, is required for efficient steroid-triggered cell death in Drosophila. Cell Death Differ 9:581-90 |
