Associate Professor, Department of Cell Biology
Our 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.
Advsr Cellular Molecular Bio Trng Program
Co Dir CMB Training Program
Inst Lecturer-Cell Bio & Histology
PhD from Columbia University
Nature communications. 2020 09 16; 11(1):4677
Neurobiology of disease. 2020 Jan 23; 104770
Computational & structural biotechnology journal. 2020 Mar; 18:1092
Journal of cell science. 2019 02 15; 132(5):
Cell reports. 2018 Feb 06; 22(6):1384-1391
Cell reports. 2017 Nov 21; 21(8):2039-2047
BMB reports. 2017 Nov; 50(11):539-545
Journal of cell science. 2017 Sep 15; 130(18):3040-3049