Department of Cell Biology
Seeley G. Mudd Building, Room 400
250 Longwood Avenue
Boston, MA 02115
Lab Members: 5 postdoctoral fellows, 4 graduate students
Visit my lab page here.
Our laboratory studies the mechanisms of cell death. We are interested in apoptotic as well as non-apoptotic cell death pathways. The goal of our research is to understand how cancer cells evade apoptotic checkpoints and how mutant proteins involved in neurodegenerative diseases activate cell death mechanisms. The tools that we use include cell biology, genetics, biochemistry and chemical biology. The research in our lab can be divided into 3 major areas:
1. Regulation of caspase activation.
Our previous works have provided important insights into multiple signaling pathways that lead to the activation of caspases and apoptosis. We are now exploring the global regulation of cellular sensitivity to apoptosis. In a genome wide siRNA screen in Drosophila cells, we have discovered a surprising role of cellular metabolism in regulating the activation of caspases. We are now exploring the molecular mechanism by which cellular metabolisms intersect with apoptosis pathways to control cell survival in tumorigenesis.
2. Regulation of autophagy.
Autophagy is a cellular mechanism mediating bulk turnover of cellular proteins and intracellular organelles. Autophagy has been shown to play a critical role in the removal of misfolded proteins. We are now exploring the global mechanisms that regulate autophagy under normal conditions because although many mammalian homologues of yeast autophagy genes have been identified, very little is known about the regulation of autophagy beyond starvation response.
3. Molecular mechanism of necroptosis, a programmed necrotic cell death pathway.
Stimulation of death receptors by agonistic ligands such as FasL and TNFa activates apoptotic cell death in apoptotic competent conditions or necrotic cell death, termed necroptosis, in apoptotic deficient conditions. Ser/Thr kinase activity of RIP1 is critical for signal transduction of necroptosis. We have identified a series of small molecules, termed necrostatins, that selectively inhibit necroptosis. We have recently shown that necrostatin-1 is an allosteric inhibitor of RIP1 kinase. We are now exploring the molecular mechanisms of neuroptosis and the roles of necroptosis in human diseases including cancers and neurodegeneration.
Potential rotation projects include learning about how to distinguish apoptotic and non-apoptotic cell death using cell biological and chemical biological tools, characterize the mechanisms of caspase activation, investigate the relationship of autophagy and cell death, etc.
Yi CH, Sogah DK, Boyce M, Degterev A, Christofferson DE, Yuan J. A genome-wide RNAi screen reveals multiple regulators of caspase activation. J Cell Biol. 2007. 179, 619-26.
Degterev A, Hitomi J, Germscheid JM, Ch’en I, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A & Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nature Chemical Biology. 2008. 4, 313-321.
Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavior RJ and Yuan J. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008. 135, 1311-23.
For a complete listing of publications click here.
Last Update: 7/26/2012