Jianke Zhang, Ph.D.
Assistant Professor
Microbiology & Immunology
Signal transduction pathways involved in apoptosis in lymphocytes and other cell types
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Our research focuses on understanding signal transduction pathways involved in apoptosis (or programmed cell death) in lymphocytes and other cell types. Apoptosis occurs at various stages during lymphocyte development, and is essential for eliminating non-functional, cancerous, or self-reactive lymphocytes. Dysregualtion of lymphocyte death may cause autoimmune diseases, leukemia, and lymphoma. We are searching, by molecular cloning and by proteomic approaches, for proteins that are involved in apoptotic-signaling networks. Physiological functions of each protein will be studied using various in vitro cell line systems, and using whole animals by transgenics and gene targeting (knockout) in mice. Our long-term goal is to identify key regulatory steps during cell death process, that are potential targets for therapeutic intervention of various diseases. Current projects in our group are as follows. FADD-mediated apoptosis. A number of related receptors, designated “Death Receptors (DR)”, initiate a potent cell death signal upon engagement with cognate ligands. Fas is essential for apoptosis of self-reactive lymphocytes. Several years ago, we isolated a Fas-Associated Death Domain (FADD) protein, which is a mediator of apoptotic signal transduction in at least five death receptor pathways, Fas, Tumor Necrosis Factor Receptor I (TNFR-I), DR3, 4, and 5. By FADD gene knockout studies in mice, we found that FADD not only is essential for apoptosis, but plays a role in cell proliferation as well. Future studies are aimed at understanding the molecular mechanisms in signal switching by FADD, between two drastically distinct pathways: life and death. TRAIL-induced cancer cell death. TRAIL is similar to Tumor Necrosis Factor (TNF), and induces apoptosis when binds to its receptors DR4 and 5. TRAIL is being vigorously studied because its cytotoxicity is restricted to tumor cells. Administration of recombinant TRAIL rejects tumor in mice with no obvious side effects. It is not fully understood how the selectivity of TRAIL-DR4/5-induced apoptosis is established. We are investigating whether the downstream FADD protein plays a regulatory role in this process. Indeed, FADD has been implicated to play a tumor suppressor role in certain genetic settings. Other cell death molecules. After membrane-proximal signaling, cell death is executed by a family of downstream killer proteases called Caspases. A number of proteins, such as FLIP, IAP, Bcl-2, and BID, regulate cell death by activating or suppressing Caspases, which are crucial in maintaining a normal physiology. We are investigating how the cell death protein network integrates various extracellular and intracellular signals in order to determine the fate of a cell.
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| Selected Publications PubMed Link For Zhang J
Zhang, H., Hou, Y-J., Han, S-Y., Zhang, E. C., Huebner, K., and Zhang, J. 2009. Mammalian nitrilase 1 homologue Nit1 is a negative regulator in T cells. Intl. Immunol. 21:691-703.
Imtiyaz, H. Z., Zhou, X., Zhang, H., Chen, D., Hu, T., and Zhang, J. Z. 2009. The death domain of FADD is essential for embryogenesis, lymphocyte development and proliferation. J. Biol. Chem. 284:9917-9926.
Zhang, H., Rosenberg. S., Coffey, F., Manser, T., He, Y-W., Hardy, R. R., Zhang, J. 2008. A role for cFLIP in B cell proliferation and stress MAP kinase regulation. J. Immunol. 182(1):207-15.
Fernandes-Alnemri, T., Wu, J., Yu, J. W., Datta, P., Miller, B., Jankowski, W., Rosenberg, S., Zhang, J., Alnemri, E.S. 2007. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 14:1590-1604.
Imtiyaz, H. Z., Rosenberg, S. Zhang, Y., Rahman, Z. S. M., Hou, Y-J., Manser, T., and Zhang, J. 2006. The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B Cells. J. Immunol. 176:6852-6861.
Tang, J., Qu, L., Zhang, J., Wang, W., Michaelson, J. S., Degenhardt, Y. Y., El-Deiry, W. S.,and Yang, X. 2006. Critical role for Daxx in regulating Mdm2. Nature Cell Biol. 8:855-862.
Zhang, Y., Rosenberg, S., Wang, H., Imtiyaz, H. Z., Hou, Y. and J. Zhang, 2005. Conditional FADD:GFP Knockout Mice Reveal FADD is Dispensable in Thymic Development but Essential in Peripheral T Cell Homeostasis. J. Immunol., 175:3033-3044.
Imtiyaz, H. Z., Zhang, Y., Zhang, J. 2005. Structural requirements forsignal-induced target binding of FADD determined by functionalreconstitution of FADD deficiency. J. Biol. Chem. 280:31360-31367.
Shen, HM, Lin, Y, Choksi S, Tran, J., Jin, T., Chang, L., Karin, M,Zhang, J., and Liu, ZG. 2004. Essential roles of receptor-interactingprotein and TRAF2 in oxidative stress-induced cell death. Mol. Cell.Biol. 24:5914-5922.
Li, W, J. Zhang, W. Yu, G. Liu, Q. Chen. 2003. Expression ofstage-specific genes during zygotic gene activation in preimplantationmouse embryos. Zoolog. Sci. 20:1389-93.
Zhang, J., Kabra, N., Cado, D., and A. Winoto. 2001. FADD-deficient Tcells exhibit Zhang, J., Kabra, N., Cado, D., and A. Winoto. 2001.FADD-deficient T cells exhibit a disaccord in regulation of the cellcycle machinery. J. Biol. Chem. 276:29815-29818.
Kabra, N., Kang, C., Hsing, L., Cado, D., Zhang, J., and A. Winoto.2001. T-cell specific FADD-deficient mice: FADD is required for early Tcell development. Proc. Natl. Acad. Sci. 98:6307-6312.
Kuang, A., Diehl, G, Zhang, J., and A. Winoto. 2000. FADD isrequired for DR4- and DR5-mediated apoptosis: Lack of TRAIL-inducedapoptosis in FADD-deficient mouse embryonic fibroblasts. J. Biol. Chem.275: 25065-25068.
Zhang, J; DeYoung, A; Kasler, HG; Kabra, NH; and etc. 1999.Receptor-mediated apoptosis in T lymphocytes. Cold Spring HarborSymposia on Quant. Biol, V64:363-371.
Zhang, J., D. Cado, A. Chen, N. Kabra, and A. Winoto. 1998. Fas-mediated apoptosis and activation-induced T-cell proliferation aredefective in mice lacking FADD/Mort1. Nature 392:296-300.
Zhang, J. and A. Winoto. 1996. A Mouse Fas-associated protein withhomology to the human Mort1/FADD protein is essential for Fas-Inducedapoptosis. Mol. Cell. Biol. 16:2756-2763.
Chan, F., J. Zhang, L. Cheng, D. Shapiro, and A. Winoto. 1995.Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitorwith homology to p16ink4. Mol. Cell. Biol. 15:2682-2688. |
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