Alexei Degterev

Office
Stearns 703C
(617) 636-0495

Lab
Stearns 703B
(617) 636-0491

Probing mechanisms of cell death using chemical, biochemical, and cell biology tools

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.

Hitomi, J., Christofferson, D.E., Ng, A., Yao, J., Degterev, A., Xavier, R.J., & Yuan, J. (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135: 1311-1323.

Miao, B., & Degterev, A. * (2008) Methods to analyze cellular necroptosis. In Apoptosis, Second Edition in Methods in Molecular Biology (Editor: P. Erhardt), Humana Press.

Ch'en, I. Beisner, D., Degterev, A., Lynch, C. Yuan, J. Hoffmann, A, & Hedrick, S.M. (2008) A second form of T cell death regulated by caspase-8. PNAS 105: 17463-17468

Korkina, O., & Degterev, A.* (2009) Cell death: apoptosis and necrosis. Invited review. Wiley Encyclopedia of Chemical Biology.

You, Z., Savitz, S., Yang, J., Degterev, A., Yuan, J., Cuny, G., Moskowitz, M., & Whalen, M (2008) Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J. Cerebral Blood Flow Metab. 28: 1564-1573.

Cuny, G.D., Degterev, A., & Yuan, J. Necroptosis – a novel cell death mechanism. Drugs of the future, 33: 225-233.

Teng, X., Keys, H., Yuan, J., Degterev, A. & Cuny, G.D. (2008) Structure-activity relationship and liver microsome stability studies of pyrrole necroptosis inhibitors. Bioorg. Med. Chem. Lett. 18: 3219-3223.

Degterev, A., & Yuan, J. (2008) Expansion and Evolution of Cell Death Programs. Nature Reviews Mol. Cell Biol. 9: 378-390.

Degterev, A.*, Hitomi, J., Ch'en, I., Germscheid, M., Korkina, O., Teng, X., Cuny, G., Yuan, C., Wagner, G., Hedrick, S., Gerber, S., Lugovskoy, A., &Yuan, J. (2008) Identification of RIP1 kinase as a cellular target of Necrostatins. Nature Chem. Biol. 4: 313-321.

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. 179: 619-626.

Teng, X., Keys, H., Jeevanandam, A., Porco, J., Degterev, A., Yuan, J., & Cuny, G. (2007) Structure activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors. Bioorg. Med. Chem. Lett. 17: 6836-6840.

Jagtap, P., Degterev, A., Choi, S., Keys, H., Yuan, J., & Cuny, G. (2007) 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. (2007) Automated neurite extraction using dynamic programming for high-throughput screening of neuron-based assays. NeuroImage, 35: 1502-1515.

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.

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