Coordination of Apoptosis and Cell Proliferation in Drosophila

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DESCRIPTION (provided by applicant): Our long-term goal is to understand how apoptosis and cell proliferation are coordinated during animal development. Proliferating cells readily undergo injury-provoked apoptosis, while postmitotic cells acquire resistance to many apoptotic stimuli. Resistance to apoptosis is important to prevent the loss of vital postmitotic cells that cannot be replaced. Conversely, facilitated cell death in proliferating tissues is thought to be an effective way to cope with cellular injury, as cell loss can be replaced through compensatory proliferation. Accordingly, coordination of cell proliferation and apoptosis is essential for maintaining animal health, and inability to coordinate these processes leads to diseases caused by excess cell proliferation as in cancer, or excess apoptosis as seen in neurodegenerative disorders. In this proposal, we will test the hypothesis that the Apoptosome, a holoenzyme complex that consists of the initiator caspase Drone and the adaptor protein Apafl, serve as a critical coordinator of apoptosis and cell proliferation. To test this, we will exploit the simple Drosophila cell death paradigm, in which Diapl (Drosophila Inhibitor of Apoptosis Protein 1) directly inhibits the Apoptosome in living cells, and the expression of Diapl antagonists Reaper, Hid and Grim precedes apoptosis to relieve this inhibition of the Apoptosome. Once Apoptosomes activate effector caspases, cells become fully committed to cell death. We will pursue three specific aims. First, we will investigate how Diapl inhibits the Apoptosome. In particular, we will test the hypothesis that Diapl directly ubiquitylates Apafl for degradation in living cells, while inactivation of Diapl in cells destined to die allow stable Apoptosome formation. Second, we will investigate the mechanism by which apoptotic cells trigger compensatory proliferation in proliferating tissues. Specifically, we will focus on the mechanism of a mitogenic signaling pathway initiated by active Apoptosomes and determine whether this underlies compensatory proliferation. Finally, we will investigate the mechanism by which postmitotic cells acquire resistance to apoptosis. Here, we will test the hypothesis that cell cycle exit enhances Apoptosome instability through ubiquitin-mediated protein degradation. Our genetic approaches in Drosophila tissues will be complemented with biochemical assays for further mechanistic studies. Progress from this research may help devise new strategies against cancer and neurodegenerative disorders.