Systematic Analysis of Cell Death Regulation
The overall objective of my research is to understand how the cell death (apoptosis) regulatory pathways are activated/utilized to mediate pro-apoptotic responses to signals such as DNA damage or virus infection. Apoptosis is a gene-controlled process that leads to the destruction of obsolete, damaged, or pathogen-infected cells. The destruction of the cell is largely initiated by the activation of a group of proteases called Caspases. Caspases are synthesized as dormant enzymes in essentially all cells, their activation is controlled by several interrelated pathways (Figure 1). Although the core cell death regulatory pathways came to light at the turn of the century (thanks to intense research interest in the field) [1], we still know little about how these pathways are utilized to mediate specific cell death responses[2].
Project 1.) Epigenetic mechanisms controlling the sensitivity to irradiation-induced cell death.
Defects in cell death regulation can leads to tumor formation and metastasis because tumor cells escape safeguarding mechanisms that eliminate malignant cells through cell death. Correspondingly, cell death is also the underlying cellular process which serves as the basis of chemo- and radio-therapy. These procedures aim at inducing cell death responses in tumor cells by applying damage-inducing chemicals or irradiation, respectively. However, we know little as to why the cellular sensitivity to irradiation-induced cell death differs dramatically among different cell/tissue types [3]. Using Drosophila as the model system, we are probing what controls the activation of upstream pro-apoptotic genes in response to irradiation. Our recent work has led to the finding that epigenetic regulation (chromatin modification) of an Irradiation Responsive Enhancer Region (IRER) upstream to the pro-apoptotic gene reaper controls the cellular sensitivity to irradiation (Figure 2). When this region is masked by “repressive” histone markers, it becomes inaccessible and renders the pro-apoptotic genes irresponsive to irradiation induced DNA damage signals. Further work is planned to identify the mechanisms that control the epigenetic regulation of IRER and whether similar mechanisms control cellular sensitivity to irradiation in mammals.
Project 2.) Systematic cross-genome comparison of cell death regulation.
Mosquito transmitted infectious diseases kills millions of people each year, mostly in under-developed countries and a large portion of the victims are children. Although much has been revealed about cell death regulation in the genetic model organism Drosophila melanogaster, it has been hard to extrapolate the findings to mosquito species. The most important pro-apoptotic genes in insects, the IAP-antagonists such as reaper and grim, are subject to rapid evolutionary diversification which makes them un-identifiable using standard sequence similarity searches. Using advanced bioinformatics strategies, we have identified several reaper/grim -like genes in mosquito genomes[4]. Interestingly, these genes are selectively activated in the mosquitoes when the pathogen infects the insect. Fully elucidating the cell death regulatory systems in mosquitoes not only will help us to understand the systematics of cell death regulation, it will also shed light on developing new strategies for blocking the infection cycle or controlling the mosquito population.
1. Danial, N.N. and S.J. Korsmeyer, Cell death: critical control points. Cell, 2004. 116(2): p. 205-19.
2. Zhou, L. and H. Steller, Distinct pathways mediate UV-induced apoptosis in Drosophila embryos. Dev Cell, 2003. 4(4): p. 599-605.
3. Zhou, L., R. Yuan, and S. Lananta, Molecular mechanisms of Irradiation induced cell death. Frontiers of Bioscience, 2003. 8:d9-19.
4. Zhou, L., G. Jiang, G. Chan, C.P. Santos, D.W. Severson, and L. Xiao, Michelob_x is the missing inhibitor of apoptosis protein antagonist in mosquito genomes. EMBO Rep, 2005. 6(8): p. 769-74.
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