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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM079425-01A1
Application #
7319607
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Zatz, Marion M
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2007-08-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$295,750
Indirect Cost
Name
New York University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Dichtel-Danjoy, M-L; Ma, D; Dourlen, P et al. (2013) Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation. Cell Death Differ 20:108-16
Domingues, C; Ryoo, H D (2012) Drosophila BRUCE inhibits apoptosis through non-lysine ubiquitination of the IAP-antagonist REAPER. Cell Death Differ 19:470-7
Ryoo, Hyung Don; Bergmann, Andreas (2012) The role of apoptosis-induced proliferation for regeneration and cancer. Cold Spring Harb Perspect Biol 4:a008797
Ryoo, Hyung Don; Baehrecke, Eric H (2010) Distinct death mechanisms in Drosophila development. Curr Opin Cell Biol 22:889-95
Malzer, Elke; Daly, Marie-Louise; Moloney, Aileen et al. (2010) Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response. J Cell Sci 123:2892-900
Kang, Min-Ji; Ryoo, Hyung Don (2009) Suppression of retinal degeneration in Drosophila by stimulation of ER-associated degradation. Proc Natl Acad Sci U S A 106:17043-8
Shapiro, Peter J; Hsu, Hans H; Jung, Heekyung et al. (2008) Regulation of the Drosophila apoptosome through feedback inhibition. Nat Cell Biol 10:1440-6