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James B. Duke Professor of Pharmacology and Cancer Biology
Provost, Duke University
Duke University School of Medicine
Durham, NC 27710
Our lab is interested in the regulation of complex cellular processes, including entry into mitosis and apoptosis (programmed cell death). We are particularly interested in understanding the regulation of apoptosis by metabolism, control of exit from mitosis, and the mechanisms underlying inhibition of apoptosis in cancer cells. We are also exploring avenues for manipulating these signaling pathways to enhance cancer therapy. To address these problems, we use mammalian systems (tissue culture and mouse models) and cell-free extracts prepared from eggs of the frog Xenopus laevis which can recapitulate cell cycle events and apoptotic processes in vitro. For the study of cell cycle events, extracts are prepared which can undergo multiple rounds of DNA replication and mitosis in vitro. For the study of apoptosis, modifications in extract preparation have allowed us to produce extracts which can accurately reproduce the biochemical events of apoptosis, including mitochondrial cytochrome c release and activation of apoptotic proteases, the caspases. These powerful in vitro approaches allow us to isolate novel cell death/cell cycle regulators which we can then assay functionally both in vitro and in intact mammalian cell systems. Using these molecular and biochemical approaches, we are working towards the elucidation of signaling pathways required for cell proliferation and cell death.
Huang, N-J, L. Zhang, W. Tang, C. Chen, C-S Yang, and S. Kornbluth (2012). The Trim 39 ubiquitin ligase inhibits APC/C Cdh1-mediated degradation of the Bax activator MOAP-1. J. Cell Biol., 197: 361-367.
Kim, J., A.B. Parrish, M. Kurokawa, C.D. Freel, J.L. Andersen, C.E. Johnson, and S. Kornbluth. (2012). MAPK-mediated suppression of cytochrome c-induced apoptosis through Rsk-mediated phosphorylation and 14-3-3ε binding of Apaf-1 EMBO J, 31: 1279-92.
Andersen, J.L.,J.W. Thompson, K.R. Lindblom, L.R. Lilley, E.S. Johnson, M.R. Buchakjian, C.D. Freel, M.A. Moseley, and S. Kornbluth. (2011). A Novel Proteomics Approach Identifies 14-3-3ζ as a target of Sirt1 in the metabolic regulation of caspase-2. Molecular Cell, 43: 834-842.
Yang, C-S., E. Gan, M.J. Thomenius, W. Tang, C.D. Freel, L.K. Nutt, and S. Kornbluth. (2010). Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of the initiator caspase Dronc. EMBO J, 29: 3196-3207.
Andersen, J.L., C.E. Johnson, C.D. Freel, A.B. Parrish, J.L. Day, M.R. Buchakjian, L. Nutt, J.W. Thompson, M.A. Moseley, and S. Kornbluth. (2009). Restraint of apoptosis during mitosis via interdomain phosphorylation of caspase-2. EMBO J., 28: 3216-27.
Nutt. L.K., M.R. Buchakjian, E. Gan, R. Darbandi, S-Y Yoon, J.Q. Wu, Y.J. Miyamoto, J. A. Gibbon, J.L Andersen, C.D. Freel, C. He, M. Kurokawa, S. Margolis, R. Fissore, and S. Kornbluth. (2009). Metabolic Control of Oocyte apoptosis mediated by 14-3-3-regulated dephosphorylation of caspase 2, Developmental Cell, 16: 856-866.
Wu, J.Q., J.Y. Guo, W. Tang, C.D. Freel, and S. Kornbluth. (2009). PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation Nature Cell Biology, 11: 644-651
Kurokawa, M.,C. Zhao, T. Reya, and S. Kornbluth. (2008). Inhibition of apoptosome by suppression of Hsp90β phosphorylation in tyrosine kinase-induced leukemias. Mol. Cell. Biol. 17:5494-5506
Guo, J.Y., A. Yamada, T. Kajino, J.Q. Wu, W. Tang, C.D. Freel, B. N. Chau, M.Z. Wang, S. Margolis, H.Y. Yoo, W.G. Dunphy, P.M. Irusta, J.M. Hardwick, and S. Kornbluth. (2008) Aven-dependent activation of ATM following DNA damage. Current Biology 18: 933-942.
C.E. Johnson, Y, Huang, A.B. Parrish, M.I. Smith, A.E. Vaughn, K.M. Wright, Q. Zhang, T. Van Dyke, R.J. Wechsler-Reya, S. Kornbluth*, and M. Deshmukh*. (2007). Differential Apaf-1 levels allow Cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues. Proc Natl Acad Sci, USA 104: 20820-5.
Freel,C.F., D.A. Richardson, M.J. Thomenius, E.C. Gan, S.R. Horn, M.R. Olsen, and S. Kornbluth. (2008). Mitochondrial localization of Reaper to promote DIAP1 degradation conferred by GH3 domain lipid interactions. J. Biol.Chem, 283: 367-379.
Tang, W., JQ. Wu, Y. Guo, D.V. Hansen, J.A. Perry, C.D. Freel, L. Nutt, P.K. Jackson, and S. Kornbluth. Promoting the Meiosis I-Meiosis II transition through Cdc2 and Mos-mediated control of Emi2 stability (2008). Mol. Biol. Cell, 8: 3536-2543.
.Wu, Q, D.V. Hansen, Y. Guo, M.Z. Wang, W. Tang, C.D. Freel, J.J. Tung, P. Jackson and S. Kornbluth. (2007). Control of Emi2 stability and activity through Mos-mediated recruitment of PP2A. Proc. Natl. Acad. Sci USA, 104: 16564-9.
Wu, Q, Y. Guo, A.Yamada, J. A. Perry, M.Z. Wang, M. Araki, C. D. Freel, J.J.. Tung, S.S. Margolis, P. K. Jackson, H. Yamano, M. Asano, and S. Kornbluth (2007). A role for Cdc2 and PP2A- mediated regulation of Emi2 in the maintenance of CSF arrest. Current Biology, 17: 1-13.
Margolis, S.S., J.A. Perry, C.M. Forester, L.K. Nutt, Y. Guo, M.J. Jardim, M.J. Thomenius, C.D. Freel, R. Darbandi, J-H Ahn, X-F Wang, S. Shenolikar, A.C. Nairn, W.G. Dunphy, W.C. Hahn, D.M. Virshup, and S. Kornbluth (2006). Role for the PP2A/B56d phosphatase in regulating 14-3-3 release from Cdc25 to control Mitosis. Cell, 127: 759-773.
Schafer, Z.T., A.B. Parrish, K.M. Wright, J.R. Marks, M. Deshmukh, and S. Kornbluth. (2006). Increased apoptosome activation and enhanced sensitivity to cytochrome c-induced apoptosis in breast cancer cells. Cancer Research, 66: 2210-2218.
Nutt., L.K., S.S. Margolis, M. Jensen, C.E. Herman, W.G. Dunphy, J.C. Rathmell, and S. Kornbluth. (2005). Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase 2. Cell, 123: 89-103.
Casaletto, J.B., L.K. Nutt, J.D. Moore, Q. Wu, L.D. Etkin, P.K. Jackson, T. Hunt, and S. Kornbluth (2005). Inhibition of the Anaphase-promoting complex by the Xnf7 ubiquitin ligase. J.Cell Biol 169:61-71.
Deming, P.B., Z.T. Schafer, J.S. Tashker, M. Potts, M.Deshmukh, and S. Kornbluth. (2004). Bcr- Abl-mediated protection from apoptosis downstream of mitochondrial cytochrome c release. Mol. Cell Biol., 24 ; 10289-10299.
Margolis, S.S., S. Walsh, D.C. Weiser, M. Yoshida, S. Shenolikar, and S. Kornbluth (2003). PP1 control of M phase entry exerted through 14-3-3-regulated Cdc25 dephosphorylation. EMBOJ, 22: 5734-5745