Steroid hormones regulate diverse metabolic, reproductive, and developmental processes throughout eukaryotes, and play an important role in human health. Relatively little is known about how steroids induce cell-specific biological responses, even though we know extensive details about how steroids activate gene transcription. We are utilizing the fruit fly, Drosophila melanogaster, as a system to study steroid-activated programmed cell death. Pulses of the steroid 20- hydoxyecdysone (ecdysone) trigger genetic regulatory hierarchies that mediate the destruction of the larval tissues by programmed cell death during metamorphosis of Drosophila from a larva to an adult. We have made progress toward understanding the mechanisms underlying steroid- regulated programmed cell death, by characterizing the relationship of genes that function in steroid-activated destruction of larval tissues. Our studies have emphasized the relationship between the ecdysone- regulated E93 gene, and the programmed cell death genes rpr and hid. E93 is unique compared to previously isolated ecdysone-regulated genes - E93 is specifically expressed in cells that are fated to die, while other early genes respond to each pulse of ecdysone in most cell types. In addition, E93 expression immediately precedes transcription of the programmed cell death genes rpr and hid. Most significantly, ectopic expression of E93 is sufficient to induce programmed cell death, and animals lacking E93 function have larval salivary glands that fail to die. Thus, E93 may be the primary stage- and tissue-specific mediator of steroid-regulated programmed cell death during Drosophila development. Here we propose: (1) detailed characterization of E93 mutants, (2) determination of the relationship between E93 and previously identified genes that function in cell death, and (3) isolation and characterization of targets of E93 that function in programmed cell death. These studies will lead to a better under- standing of this novel cell death pathway, and how steroids activate programmed cell death in higher eukaryotes.
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