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Hyung Don RyooAssociate Professor, Department of Cell Biology
Co Dir CMB Training Program
Advsr Cellular Molecular Bio Trng Program
Inst Lecturer-Cell Bio & Histology
550 First Avenue
New York, NY 10016
Research SummaryOur laboratory is interested in understanding the basic mechanisms of apoptosis during animal development and in diseases. Our strategy is to use the genetic and cell biological tools of Drosophila as a model system.
Apoptosis is a morphologically distinct form of cell death that is programmed to sculpt body structures, maintain proper numbers of cells during development and eliminate damaged and potentially dangerous cells. Apoptosis is found defective in most cancers, and excess apoptosis underlies many neurodegenerative disorders. A critical event in apoptosis is the activation caspases, a family member of the Cysteine proteases that reside in living cells as inactive zymogens and activated in cells that undergo apoptosis. For proper apoptosis regulation, caspases are extensively regulated, both through its activators such as Apaf-1/cytochrome c and through its inhibitors such as IAPs (Inhibitor of Apoptosis Proteins). In Drosophila, various cell death stimuli converge on the transcriptional and post-transcriptional regulation of IAP inhibitors Reaper, Hid and Grim.
Our research program can be subdivided into two major areas. Our first area of interest is to understand the mechanism of caspase regulation. We have previously demonstrated that Drosophila IAP1 (DIAP1) acts as a ubiquitin-ligase that targets apical caspase Dronc in living cells, and undergoes auto-ubiquitylation during apoptosis (Ryoo et. al., 2002; Ryoo et. al., 2004). Furthermore, we showed that DIAP1 inhibition, which occurs in cells doomed to die, leads to the induction of secretory factors DPP and WG. In turn, these secreted factors promote the proliferation and growth of neighboring cells. We have proposed that this regulatory mechanism contributes to apoptosis-induced compensatory cell proliferation (Ryoo et. al., 2004). We plan to further investigate the mechanistic basis of coordination between apoptosis and cell proliferation with a special focus on Diap1 and caspases. Progress in this area may enhance our understanding of how tissue size is regulated during animal development and in cancer (Ryoo et. al., 2003).
Our second research program is aimed at understanding how endoplasmic stress (ER-stress) activates apoptosis. ER-stress is frequently caused by unfolded proteins in the ER, and is thought to be the cause of a wide variety of disorders, including alzheimer's disease, parkinson's disease, retinitis pigmentosa, multiple myeloma and diabetes. Although apoptosis is a pathologically relevant outcome of ER-stress, how caspases become activated under these conditions remains poorly characterized. We have begun investigating the Drosophila genes that make up the cellular response machinery to ER-stress, also known as the Unfolded Protein Response (UPR). Through this effort, we found that the Drosophila xbp1 mRNA undergoes unconventional splicing in response to ER-stress, similar to those found in other organisms. This property was used to generate an ER-stress sensor where GFP is expressed in frame only after xbp1 mRNA splicing. Significantly, xbp1 splicing and ER-chaperone induction occurs in the Drosophila model for the Autosomal Dominant Retinitis Pigmentosa (ADRP), where the expression of mutant rhodopsin-1 molecules leads to late onset retinal degeneration. These developments provide a basis to investigate how ER-stress activates apoptosis in Drosophila disease models (Ryoo et. al., 2007). Ongoing efforts aim to examine existing hypotheses and to identify new components linking ER-stress and caspase activation.
Adaptive Preconditioning in Neurological Diseases - Therapeutic Insights from Proteostatic Perturbations
Mollereau, B; Rzechorzek, N M; Roussel, B D; Sedru, M; Van den Brink, D; Bailly-Maitre, B; Palladino, F; Medinas, D B; Domingos, P M; Hunot, S; Chandran, S; Birman, S; Baron, T; Vivien, D; Duarte, C B; Ryoo, H D; Steller, H; Urano, F; Chevet, E; Kroemer, G; Ciechanover, A; Calabrese, E J; Kaufman, R J; Hetz, C. Adaptive Preconditioning in Neurological Diseases - Therapeutic Insights from Proteostatic Perturbations. Brain research. 2016 Mar 2;1648(Pt B):603-616 (2009212)
Long and short (timeframe) of endoplasmic reticulum stress-induced cell death
Ryoo, Hyung Don. Long and short (timeframe) of endoplasmic reticulum stress-induced cell death. FEBS journal. 2016 Jun 6;283(20):3718-3722 (2112192)
Detection of Cell Death in Drosophila Tissues
Vasudevan, Deepika; Ryoo, Hyung Don. Detection of Cell Death in Drosophila Tissues. Methods in molecular biology. 2016 ;1419:131-144 (2091912)
Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant
Jang, Bo-Yun; Ryoo, Hyung Don; Son, Jaekyoung; Choi, Kyung-Chul; Shin, Dong-Myoung; Kang, Sang-Wook; Kang, Min-Ji. Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant. International journal of molecular medicine. 2015 Feb 25;35(4):870-876 (1473962)
A Drosophila Reporter for the Translational Activation of ATF4 Marks Stressed Cells during Development
Kang, Kwonyoon; Ryoo, Hyung Don; Park, Jung-Eun; Yoon, Jee-Hyun; Kang, Min-Ji. A Drosophila Reporter for the Translational Activation of ATF4 Marks Stressed Cells during Development. PLoS one. 2015 May 15;10(5):e0126795-e0126795 e0126795 (1579622)