title_microbiology
Faculty & Research
Sankar Ghosh, Ph.D.

Sankar Ghosh, Ph.D.
Silverstein and Hutt Family Professor of Microbiology & Immunology and Chairman of the Department of Microbiology & Immunology
Ph.D., Albert Einstein College of Medicine.

Inflammation and immune response

Phone: 212-304-5257
Fax: 212-305-1468
Email: sg2715@columbia.edu

Research

Research in our laboratory is focused on understanding how engagement of receptors of both the innate and adaptive immune system lead to the activation of appropriate cellular responses through the inducible transcription factor, NF-kB. NF-kB plays a critical role in regulating the expression of a large number of genes involved in immune, inflammatory and apoptotic processes. NF-kB can be activated by different stimuli such as microbial products, proinflammatory cytokines, T and B cell mitogens and physical and chemical stresses. NF-kB in turn regulates the inducible expression of many cytokines, chemokines, adhesion molecules, acute phase proteins and anti-microbial peptides. Therefore NF-kB plays a central, evolutionarily conserved role in coordinating immune and inflammatory responses. In unstimulated cells, NF-kB is retained in the cytoplasm through its interaction with the inhibitory IkB proteins. Stimulation of cells with different inducers leads to the phosphorylation and subsequent degradation of the IkB proteins. Upon degradation of IkB, the free NF-kB enters the nucleus, however translocation of NF-kB to the nucleus is, in itself, not sufficient to drive transcription of target genes. Instead, specific phosphorylation of one of the NF-kB subunits, p65/RelA, is required for both efficient DNA-binding and transcriptional activity of the nuclear NF-kB.

We wish to understand the mechanisms that operate in the signal transduction pathways that lead to NF-kB activation, as well as the regulatory mechanisms that control the activity of NF-kB in the nucleus. Specific projects that are underway at present are listed below.

1. Understanding the mechanism by which signals from Toll/IL-1 receptors, TNF receptor and the T-cell receptor lead to NF-kB activation.
2. Characterizing the mechanism by which the transcriptional activity of nuclear NF-kB is regulated.
3. Exploring the dysregulation of NF-kB activity in diseases such as arthritis and cancer.
4. Understanding the biology of novel Toll-like receptors in response to infection.

Recent and Notable Articles

  1. Kopp, E. and Ghosh, S. Inhibition of NF-kB by sodium salicylate and aspirin. Science 265, 956-959 (1994)
  2. Thompson, J.E., Phillips, R.J., Erdjument-Bromage, H., Tempst, P., and Ghosh, S. IkB-ß regulates the persistent response in a biphasic activation of NFk-B. Cell 80, 573-582 (1995)
  3. Ghosh, G., Van Duyne, G., Ghosh, S., and Sigler, P.B. Structure of NF-kB p50 homodimer bound to a kB Site. Nature 373, 303-310 (1995)
  4. Beg, A.A., Sha, W.C., Bronson, R.T., Ghosh, S., and Baltimore, D. Embyonic lethality and liver degeneration in mice lacking the RelA component of NF-kB. Nature 376, 167-170 (1995)
  5. Zhong, H., SuYang, H., Erdjument-Bromage, H., Tempst, P., Ghosh, S. The transcriptional activity of NF-kB is regulated by IkB-associated PKAc subunit through a cyclic AMP independent mechanism. Cell 89, 413-424 (1997)
  6. Zhong, H., Voll, R. E. and Ghosh, S. Phosphorylation of NF-kB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the co-activator CBP/p300. Molecular Cell 1, 661-671 (1998)
  7. Medzhitov, R., Kopp, E.B., Ghosh, S. and Janeway, C.A. MyD88 is a common intermediate in the IL-1 and Toll signal transduction pathways. Molecular Cell 2, 253-258 (1998)
  8. Kopp, E., Medzhitov, R., Carothers, J., Xiao, C., Douglas, I., Janeway, C. A. and Ghosh, S. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes & Development 13, 2059-2071 (1999)
  9. Fenwick, C., Na, S-Y., Voll, R. E., Zhong, H., S-Y. Im, Lee, J. W. and Ghosh, S. A sub-class of Ras proteins that regulate the degradation of IkB. Science 287, 869-873 (2000)
  10. Li, B., Yu, H., Zheng, W., Voll, R., Na, S., Roberts, A., Williams, D. A., Davis, R. J., Ghosh, S. and Flavell, R. A. Role of the guanosine triposphatase Rac2 in T helper 1 cell differentiation. Science 288, 2219-2222 (2000)
  11. Voll, R.E., Jimi, E., Phillips, R.J., Barber, D.F., Rincon. M., Hayday, A.C., Flavell, R.A., and Ghosh. S. NFk-B Activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13, 677-689 (2000)
  12. May, M. J., D'Acquisto, F., Madge, L. A., Gloeckner, J., Pober, J. S. and Ghosh, S. Selective inhibition of NFk-B activation by a peptide that blocks the interaction of NEMO with the IkB kinase complex. Science 289,1550-1554 (2000)
  13. Zhong, H., May, M. J., Jimi, E. and Ghosh, S. Phosphorylation of nuclear NF-kB governs its association with either HDAC-1 or CBP/p300: a mechanism for regulating the transcriptional activity of NF-kB. Molecular Cell 9, 625-636 (2002)
  14. Xiao, C., Shim, J-H., Kluppel, M., Zhang, S-M., Dong, C., Flavell, R.A., Fu, X-Y., Wrana, J. L., Hogan, B. L. M., and Ghosh S. Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis. Genes & Development 17, 2933-2949 (2003)
  15. Zhang, D., Zhang, G., Hayden, M. S., Greenblatt, M.S., Bussey, C., Flavell, R. A. and Ghosh, S. A novel Toll-like receptor that prevents infection of kidneys by uropathogenic bacteria. Science 303, 1522-1526 (2004)
  16. Jimi, E., Aoki, K., Saito, H., D'Acquisto, F., May, M. J., Ichiro Nakamura, I., Sudo, T., Ohya, K., and Ghosh, S. Selective inhibition of NF-kB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nature Medicine 10, 617-624 (2004)
  17. Lee, K.-Y., D'Acquisto, F., Hayden, M. S., Shim, J.-H., and Ghosh, S. Protein Kinase PDK1 Nucleates T-cell Receptor-Induced Signaling Complex for NF-kB Activation. Science 308, 114-118 (2005)
  18. Yarovinsky, F., Zhang, D., Andersen, J. F., Bannenberg, G. L., Serhan, C.N., Hayden, M.S., Hieny, S., Sutterwala, F., Flavell, R. A., Ghosh, S. and Sher, A. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308, 1626-1629 (2005)
  19. Shim, J, H, Xiao, C, Paschal, A., Bailey, S. T., Rao, P., Hayden, M. S., Lee, K.Y., Bussey, C., Steckel, M., Tanaka, N., Akira, S., Yamada, G., Matsumoto, S. and Ghosh, S. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes & Development 19, 2668-2681 (2005)
  20. Dong, J., Jimi, E., Zhong, H., Hayden, M. S. and Ghosh S. Epigenetic regulation of NF-kB dependent gene expression. Genes & Development 22, 1159-1173 (2008)
  21. Jimi, E., Voll, R. E., Strickland, I., Long, M. and Ghosh, S. Differential role of NF-kB in selection and survival of CD4 and CD8 thymocytes. Immunity 29, 523-537 (2008)
  22. Hayden, M.S. and Ghosh, S. Shared principles in NF-kB signaling. Cell 132, 344-362 (2008)
  23. Hayden, M. S. and Ghosh, S. New Regulators of the NF-kB pathway. Nature Reviews Immunology 8, 837-848(2008)
  24. Park, S.-G., Schulze-Luehrman, J., Hayden, M. S., Hashimoto, N., Ogawa, W., Kasuga, M. and Ghosh, S. PDK1 integrates TCR and CD28 signaling to NF-kB. Nature Immunology, 10, 158-166 (2009)
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