Phone: (303) 492-0271
Ph.D., Columbia University, 1993
Mechanisms of the regulation activation and execution of programmed cell death in the nematode C. elegans and in mammals.
Programmed cell death is a naturally occurring cellular process in which cells self-destruct by activation of an intrinsic suicide program. Like cell proliferation, cell death is an essential aspect of animal development and homeostasis. Both processes are tightly controlled so that cell numbers in tissues and organs are maintained at appropriate levels. Misregulation of programmed cell death may underlie many human diseases including cancers, autoimmune disorders, neurodegenerative disorders and immunodeficiency diseases.
We use the nematode Caenorhabditis elegans as a model system to study how programmed cell death is regulated, activated and executed, because C. elegans is uniquely amenable to both molecular genetic and biochemical analysis and because the cell death pathway is conserved between nematodes and mammals.The study of cell death in nematodes can provide crucial information toward understanding cell death mechanisms in humans and, ultimately, may identify means to combat human diseases caused by inappropriate apoptosis.
Genetic studies in C. elegans have identified many genes that are important for five sequential steps of programmed cell death (see Figure): the specification of which cells should die, the activation of the cell death program, the execution of the cell-killing process, the engulfment of cell corpses, and finally, the degradation of cellular debris. Several genes have been cloned and found to encode proteins homologous to factors involved in mammalian cell death, including two transcription factors (ces-1 and ces-2), a BH3-domain-containing cell-death initiator (egl-1), a cysteine protease that executes the suicide program (ced-3), and a cell-death inhibitor similar to the mammalian cell-survivor factor Bcl-2 (ced-9). The CED-3 death protease is particularly interesting. CED-3 is first synthesized as an inactive proenzyme and later is activated through proteolysis, which then triggers systematic and orderly cell disassembly. Thus the study of how CED-3 is activated and how it acts to cause cell death offers a great paradigm for studying the regulation and execution of programmed cell death. Using a combination of genetic, molecular, biochemical and structural biological aproaches, we focus on addressing three key issues about the CED-3 death protease: 1) how is CED-3 expressed and activated in the right cell and at the right time? 2) what are the substrates of the CED-3 death protease? and 3) how do proteolytic cleavages of these substrates by CED-3 elicit the cellular and morphological changes that lead to the demise of a cell?
We have performed both genetic and biochemical screens to identify proteins that regulate the activation or activity of the CED-3 death protease and proteins that are substrates of the CED-3 death protease. So far, we have identified at least eight new genes (cps-1 to cps-8; CED-3 protease suppressors) that act downstream of the CED-3 death protease to cause cell death and at least seven new genes that function to activate the CED-3 death protease in specific subsets of cells. We have also initiated biochemical and structural analysis of crucial protein interactions and mechanisms that are involved in the activation of the CED-3 death protease. Molecular genetic characterization and biochemical analysis of these ten new cell-death genes will help elucidate how programmed cell death is regulated, activated, and executed in general.
Role of C. elegans TAT-1 protein in maintaining plasma membrane phosphatidylserine asymmetry.
Darland-Ransom, M, Wang, X, Sun, C, Mapes, J, Gengyo-Ando, K, Mitani, S, and Xue, D Science, 320(5875):528-31. 2008
Caenorhabditis elegans drp-1 and fis-2 regulate distinct cell-death execution pathways downstream of ced-3 and independent of ced-9.
Breckenridge, DG, Kang, B, Kokel, D, Mitani, S, Staehelin, LA, and Xue, D Mol Cell, 31(4):586-97. 2008
Inhibition of CED-3 zymogen activation and apoptosis in Caenorhabditis elegans by caspase homolog CSP-3.
Geng, X, Shi, Y, Nakagawa, A, Yoshina, S, Mitani, S, Shi, Y, and Xue, D Nat Struct Mol Biol, 15(10):1094-101. 2008
Caspase-dependent conversion of Dicer ribonuclease into a death-promoting deoxyribonuclease.
Nakagawa, A, Shi, Y, Kage-Nakadai, E, Mitani, S, and Xue, D Science, 328(5976):327-34. 2010
Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor.
Wang, X, Li, W, Zhao, D, Liu, B, Shi, Y, Chen, B, Yang, H, Guo, P, Geng, X, Shang, Z, Peden, E, Kage-Nakadai, E, Mitani, S, and Xue, D Nat Cell Biol, 12(7):655-64. 2010