The Regulation of Drosophila Inhibitor of Apoptosis Protein I in Apoptosis and Cell Survival.

Abstract

Apoptosis is an evolutionarily conserved, actively regulated cell death process that plays an essential role during development and in adulthood. It is subject to negative regulation by Inhibitor of Apoptosis Proteins (IAPs). Accumulated evidence suggests that the regulation of IAPs is important for development and homeostasis, as the function of IAPs has to be antagonized to allow the occurrence of apoptosis, while the activation of IAPs promotes cell survival. In this dissertation, the regulation of IAP proteins was studied in apoptotic and surviving cells respectively. Specifically, the regulation mechanism of Drosophila IAP1 (DIAP1) was systematically investigated in developmental apoptosis in the fly pupal eye. DIAP1 binds to caspases and inhibits their activity. IAP antagonists RHG proteins can induce apoptosis by binding to DIAP1 and liberating the bound caspases. In addition, some RHG proteins can induce DIAP1 degradation. Results in this dissertation demonstrated significant down-regulation of DIAP1 protein in perimeter ommatidia that undergo apoptosis. Further investigation suggests that both liberation of caspases and degradation of DIAP1 are required for timely initiation and progression of apoptosis in the developing fly eye. Strikingly, the E3 ligase activity of DIAP1’s RING domain was shown to be dispensable for RHG-mediated degradation. In contrast, RHG may regulate DIAP1 through initiator caspase Dronc and the fly Apaf-1 homologue Dark. The Drosophila casein kinase Iε/δ, known as Discs overgrown (Dco) was shown to be a novel factor that is required for maintaining low levels of apoptosis in fast growing tissues during development. Dco also promotes cell division/growth in addition to its role in cell survival. Further investigation strongly suggested that Dco coordinates tissue size by stimulating cell division/growth and blocking apoptosis via activation of DIAP1 expression. Interestingly, Gilgamesh (Gish), the fly casein kinase Iγ, may regulate DIAP1 too. It is suggested that Gish and Dco may be functionally redundant.