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Office Lab
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Alexei Degterev Lab Webpage (under construction)
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Office Lab
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Programmed cell death (PCD) mechanisms play key roles in the normal functioning of the organism and in multiple pathologies. My lab is focusing on characterization of basic mechanisms of PCD using a multidisciplinary approach that combines chemical biology, based on the systematic selection and use of small molecules to dissect intrinsic regulatory networks, with cell biological and biochemical approaches. We hope that our approach will not only produce exciting new insights into endogenous cellular regulatory networks, but also provide novel therapeutic agents to target cell death associated with human pathologies. Currently the projects in the lab focus on two major subjects.
We have recently defined a new mechanism of regulated necrosis-like cell death, which we termed necroptosis, and reported that it prominently contributes to ischemic injury in various tissues. We are focusing on: 1) characterization of the protein mediators of necroptosis, identified using chemical and proteomics methods, 2) characterization of cytoprotective properties and mechanisms of action of specific small molecule inhibitors of necroptosis, the necrostatins, developed by the lab, and 3) analysis of the role of necroptosis during development and in homeostasis of the mammalian immune system using transgenic approaches.
In addition, my lab is interested in dissecting the signaling events triggered by phosphatidylinositol 3-kinase through its lipid product, phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 signaling plays a central role in the regulation of cell death, proliferation, cell motility and many other cellular functions. In particular, this pathway is very frequently dysregulated in cancers through genetic inactivation of the lipid phospatase PTEN. We have identified two structurally unrelated small molecule inhibitors, termed PITs, of PIP3 interactions with its intracellular receptors, plekstrin homology (PH) domains, and are characterizing the induction of cell deathby these molecules. We are focusing on: 1) defining cellular regulatory steps affected by PITs, 2) structural analyses of the PIT/PH interactions, 3) identification of specific PH domain-containing proteins contributing to various functional outcomes of PIP3 signaling using small molecule inhibitor-derived probes, and 4) characterization of the anti-tumor activities of PITs in vivo.
Lab members
Benchun Miao - Postdoctoral
Associate
Olga Korkina - Postdoctoral Associate
Megan Germscheid - Research
Technician
Publications
Degterev, A., Hitomi, J., Germscheid, M., Korkina, O., Teng, X., Cuny, G., Gerber, S., Lugovskoy, A., & Yuan, J. (2007) Identification of specific cellular target of necrostatins. Nature Chemical Biology. Under review.
Teng, X., Degterev, A., Keys, H., Jeevanandam, A., Porco, J., Yuan, J., & Cuny, G. (2007) Structure activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors. Bioorg. Med. Chem. Lett. In Press.
Yi, C., Sogah, D., Boyce, M., Degterev, A., Christofferson, D., & Yuan, J. (2007) A genome-wide RNAi screen reveals critical regulators of caspase activation. J. Cell Biol. In Press.
Wang, K., Li, J., Degterev, A., Hsu, E., Yuan, J., & Yuan, C. (2007) Structure-activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5. Bioorg. Med. Chem. Lett. 17: 1455-1465.
Moerke, N.J., Aktas, H., Chen, H., Cantel, S., Reibarkh, M.Y., Fahmy, A., Gross, J.D., Degterev, A., Yuan, J., Chorev, M., Halperin, J.A., & Wagner, G. (2007) A small molecule inhibitor of the eIF4E/eIF4G interaction with anti-tumour activity. Cell 128: 257-267.
Zhou, X., Degterev, A., Lipinski, M., Adjeroh, D., Yuan, J., & Wong, S.T. (2007) Automated neurite extraction using dynamic programming for high-throughput screening of neuron-based assays. NeuroImage 35: 1502-1515.
Jagtap, P., Degterev, A., Choi, S., Yuan, J., & Cuny, G. (2006) Structure activity relationship study of tricyclic necroptosis inhibitors. J. Med. Chem. 50: 1886-1895.
Zhang, Y., Zhou, X., Degterev, A., Lipinski, M., Adjeroh, D., Yuan, J., & Wong, S.T. (2006) A Novel Tracing Algorithm for High Throughput Imaging Screening of Neuron Based Assays. J. Neurosci. Methods 160: 149-162.
Shibata, Mamoru; Lu, Tao; Furuya, Tsuyoshi; Degterev, Alexei; Mizushima, Noboru; Yoshimori, Tamotsu; MacDonald, Marcy; Yankner, Bruce; Yuan, Junying. (2006). “Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1.” Journal of Biological Chemistry 2006 March 6; [Epub ahead of print]
Xiong, Guanglei; Zhou, Xiaobo; Degterev, Alexei; Ji, Liang; Wong, Stephen T.C. (2006). Automated neurite labeling and analysis in fluorescence microscopy images. Cytometry Part A 69A(6): 494-505
Moerke, N.J, Chen, H., Harbinski, F., Gross, J.D., Degterev, A., Yuan, J., Aktas, H., Halperin, J.A., & Wagner, G. (2005) A novel small molecule inhibitor of eIF4E/eIF4G association and cap-dependent translation. Submitted.
Teng, X., Degterev, A., Jagtap, P., Xing, X., Choi, S., Denu, R., Yuan, J., & Cuny, G.D. (2005) Structure-activity relationship study of novel necroptosis inhibitors. Bioorg. Med. Chem. Lett. 15: 5039-5044
Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G., Mitchison, T., Moskowitz, M., & Yuan, J. (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology 1: 112-119.
Lugovskoy, A., Degterev, A., Fahmy, A., Zhou, P., Gross, G., Yuan, J., & Wagner, G. A novel approach for characterizing protein ligand complexes: Molecular basis of specificity of small-molecule Bcl-2 inhibitors. (2002) J. Am. Chem. Soc. 124: 1234-1240.
Degterev, A., Lugovskoy, A., Cardone, M., Mulley, B., Wagner, G., Mitchison, T. & Yuan, J. (2001) Identification of small-molecule inhibitors of interaction between BH3 domain and Bcl-xL. Nature Cell Biology.3: 173-182.
Degterev, A. & Foster J.A. (1999) The role of NF-1 factors in regulation of elastin gene transcription. Matrix Biol. 18: 295-307.
Bogdanova, S.L., Degtyarev, A.I., Baranov, P.V., Dokudovskaya, S.S., Lavrik, I.N., Dontsova, O.A., Oretskaya, T.S., Krynetskaya, N.F., Shabarova, N.F. & Bogdanov, A.A. (1995) Site-Directed Cleavage of Single Internucleotide Bonds in Ribosomal RNA. Biochemistry ( Moscow), 60: 217-224.
Reviews:
Boyce, M., Degterev, A., & Yuan, J. (2004) Caspases: an ancient cellular sword of Damocles. Cell Death Differ. 11: 29-37
Lipinski, M., Degterev, A., & Yuan, J. (2003) Diversity in the mechanisms of neuronal cell death. Neuron. 40: 401-413.
Degterev, A., Boyce, M., & Yuan, J. (2003) A decade of caspases. Oncogene.22: 8543-8567.
Degterev, A., Boyce, M., & Yuan, J. (2001) The channel of death. J Cell Biol. 155: 695-698
Degterev, A, & Yuan, J. (1999) The new savior for neurons. Nature Neurosci. 2: 930-932