Biomedical Research Education & Training
Faculty Member

Ballard, Dean Williams, Ph.D.
Professor of Pathology, Microbiology and Immunology

Lab Url: N/A

Phone Number: 615-343-1918

Email Address: dean.ballard@vanderbilt.edu

Ballard, Dean's picture
Academic history
B.S., Marshall
M.S., Illinois, Urbana
Ph.D., Illinois, Urbana

Office Address   Mailing Address

A4301 Medical Center North

A-5301 MCN Vanderbilt University School of Medicine 2363


Research Specialty
Molecular Mechanisms in Normal and Malignant T Cell Growth; Regulatory Protein Modifications in Immunoreceptor Signaling

Research Description
During an immune response, antigen-stimulated T lymphocytes execute a genetic program that mediates their clonal expansion and the acquisition of specific effector functions. This activation process involves the transient expression of select transcription units required for cell-cycle progression. In lymphocytes harboring the type 1 human immunodeficiency virus (HIV-1), activation of this program concomitantly triggers the induction of retroviral gene expression, assembly of infectious viral particles, and T cell death. In sharp contrast, infection with the type 1 human T-cell leukemia virus (HTLV-1) leads to the constitutive expression of these growth-related gene products and the onset of neoplastic transformation.

Our laboratory is investigating the intracellular events that initiate these divergent processes and the host transcriptional machinery that regulates the relevant genes. A major link between these processes is an inducible transcription factor called NF-kB. In contrast to its transient pattern of expression in normal T lymphocytes, NF-kB is constitutively activated in cells expressing the Tax transforming protein of HTLV-1. We have recently explored (i) the mechanism of NF-kB action, (ii) the biochemical events that mediate NF-kB induction during T cell activation, and (iii) the host regulatory components that couple HTLV-1 Tax to this signal-dependent pathway.

In resting T cells, NF-kB is trapped in the cytoplasm by an inhibitor called IkB. During the process of cellular activation, IkB is phosphorylated, ubiquitinated, and degraded, thus permitting NF-kB access to the nuclear compartment. This information led us to design dominant forms of IkB which escape from signal-dependent inactivation and repress NF-kB in a constitutive manner. These IkB "super-repressors" have provided powerful genetic tools to dissect the role of NF-kB in both B and T cell development. In combination with differential display technology, we have also used these IkB super-repressors to capture immediate-early genes under NF-kB control, one of which functions to regulate the apoptotic response.

More recent studies demonstrated that the HTLV1 Tax protein binds to a cellular IkB kinase, called IKK, resulting in its persistent funtional expression. These results provide a unifying molecular explanation for the constitutive activation of NF-kB in HTLV1-infected cells. We are currently investigating how the formation of Tax/IKK complexes leads to persistent NF-kB signaling at the level of post-translational modifications. These studies are focused on the role of both phosphorylation and ubiquitination in IKK subunit regulation, which should yield insights into the mechanisms underlying chronic versus transient NF-kB signaling.

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Publications
Hansberger, MW, Campbell, JA, Danthi, P, Arrate, P, Pennington, KN, Marcu, KB, Ballard, DW, Dermody, TS. IkappaB kinase subunits alpha and gamma are required for activation of NF-kappaB and induction of apoptosis by mammalian reovirus. J Virol, 81(3), 1360-71, 2007 PMCID:1797491

Zhao T, Yang L, Sun Q, Arguellow M, Ballard DW, Hiscott J, and Lin R . NEMO has an essential function in the regulation of type I interferon production. Nature Immunol, 8(6), 592-600, 2007

O''Donnell, SM, Holm, GH, Pierce, JM, Tian, B, Watson, MJ, Chari, RS, Ballard, DW, Brasier, AR, Dermody, TS. Identification of an NF-kappaB-dependent gene network in cells infected by mammalian reovirus. J Virol, 80(3), 1077-86, 2006 PMCID:1346919

Carter, RS, Pennington, KN, Arrate, P, Oltz, EM, Ballard, DW. Site-specific monoubiquitination of IkappaB kinase IKKbeta regulates its phosphorylation and persistent activation. J Biol Chem, 280(52), 43272-9, 2005

Kray, AE, Carter, RS, Pennington, KN, Gomez, RJ, Sanders, LE, Llanes, JM, Khan, WN, Ballard, DW, Wadzinski, BE. Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A. J Biol Chem, 280(43), 35974-82, 2005

Liu, Danya, Liu, Xue Yan, Robinson, Daniel, Burnett, Christie, Jackson, Charity, Seele, Louis, Veach, Ruth Ann, Downs, Sheila, Collins, Robert D., Ballard, Dean W., Hawiger, Jacek. Suppression of staphylococcal enterotoxin B-induced toxicity by a nuclear import inhibitor. J Biol Chem, 2004

Carter, Robert S, Pennington, Kevin N, Ungurait, Bradley J, Arrate, Pia, Ballard, Dean W. Signal-induced ubiquitination of I kappaB Kinase-beta. J Biol Chem, 278(49), 48903-6, 2003

Carter, Robert S, Pennington, Kevin N, Ungurait, Bradley J, Ballard, Dean W. In vivo identification of inducible phosphoacceptors in the IKKgamma/NEMO subunit of human IkappaB kinase. J Biol Chem, 278(22), 19642-8, 2003

Mora, A L, Corn, R A, Stanic, A K, Goenka, S, Aronica, M, Stanley, S, Ballard, D W, Joyce, S, Boothby, M. Antiapoptotic function of NF-kappaB in T lymphocytes is influenced by their differentiation status: roles of Fas, c-FLIP, and Bcl-xL. Cell Death Differ, 10(9), 1032-44, 2003

Ballard, D W. Molecular mechanisms in lymphocyte activation and growth. Immunol Res, 23(2-3), 157-66, 2001

Carter, R S, Geyer, B C, Xie, M, Acevedo-Su?!rez, C A, Ballard, D W. Persistent activation of NF-kappa B by the tax transforming protein involves chronic phosphorylation of IkappaB kinase subunits IKKbeta and IKKgamma. J Biol Chem, 276(27), 24445-8, 2001

McKinsey, T A, Chu, Z, Tedder, T F, Ballard, D W. Transcription factor NF-kappaB regulates inducible CD83 gene expression in activated T lymphocytes. Mol Immunol, 37(12-13), 783-8, 2001

Connolly, J L, Rodgers, S E, Clarke, P, Ballard, D W, Kerr, L D, Tyler, K L, Dermody, T S. Reovirus-induced apoptosis requires activation of transcription factor NF-kappaB. J Virol, 74(7), 2981-9, 2000 PMCID:111796

Jo, H, Zhang, R, Zhang, H, McKinsey, T A, Shao, J, Beauchamp, R D, Ballard, D W, Liang, P. NF-kappa B is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis. Oncogene, 19(7), 841-9, 2000

Petro, J B, Rahman, S M, Ballard, D W, Khan, W N. Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med, 191(10), 1745-54, 2000 PMCID:2193161

Bash J, Zong WX, Banga S, Rivera A, Ballard DW, Ron Y, Gelinas C. Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. EMBO J, 18:(10), 2803-2811, 1999

Bendall, H H, Sikes, M L, Ballard, D W, Oltz, E M. An intact NF-kappa B signaling pathway is required for maintenance of mature B cell subsets. Mol Immunol, 36(3), 187-95, 1999

Byrd, V M, Ballard, D W, Miller, G G, Thomas, J W. Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells. J Immunol, 162(10), 5853-9, 1999

Chu, Z L, Shin, Y A, Yang, J M, DiDonato, J A, Ballard, D W. IKKgamma mediates the interaction of cellular IkappaB kinases with the tax transforming protein of human T cell leukemia virus type 1. J Biol Chem, 274(22), 15297-300, 1999

Devalaraja, M N, Wang, D Z, Ballard, D W, Richmond, A. Elevated constitutive IkappaB kinase activity and IkappaB-alpha phosphorylation in Hs294T melanoma cells lead to increased basal MGSA/GRO-alpha transcription. Cancer Res, 59(6), 1372-7, 1999

Hawiger, J, Veach, R A, Liu, X Y, Timmons, S, Ballard, D W. IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. Blood, 94(5), 1711-6, 1999

Mori N, Fujii M, Ikeda S, Yamada Y, Tomonaga M, Ballard DW, Yamamoto N. Constitutive activation of NF- kappaB in primary adult T-cell leukemia cells. Blood, 59(6), 1372-1377, 1999

Chu, Z L, DiDonato, J A, Hawiger, J, Ballard, D W. The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IkappaB kinases containing IKKalpha and IKKbeta. J Biol Chem, 273(26), 15891-4, 1998

Mori, N., Mukaida, N., Ballard, D.W., Matsushima, K., and Yamamoto, N. Human T-cell leukemia virus type I Tax transactivates human interleukin-8 gene through acting concurrently on AP-1 and nuclear factor kB-like sites. Cancer Res. , 58:(3993), 1998

Bendall, H H, Scherer, D C, Edson, C R, Ballard, D W, Oltz, E M. Transcription factor NF-kappaB regulates inducible Oct-2 gene expression in precursor B lymphocytes. J Biol Chem, 272(46), 28826-8, 1997

Boothby, M R, Mora, A L, Scherer, D C, Brockman, J A, Ballard, D W. Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-kappaB. J Exp Med, 185(11), 1897-907, 1997 PMCID:2196335

Chu, Z L, McKinsey, T A, Liu, L, Gentry, J J, Malim, M H, Ballard, D W. Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci U S A, 94(19), 10057-62, 1997 PMCID:23303

McKinsey, T A, Chu, Z L, Ballard, D W. Phosphorylation of the PEST domain of IkappaBbeta regulates the function of NF-kappaB/IkappaBbeta complexes. J Biol Chem, 272(36), 22377-80, 1997

Chu, Z L, McKinsey, T A, Liu, L, Qi, X, Ballard, D W. Basal phosphorylation of the PEST domain in the I(kappa)B(beta) regulates its functional interaction with the c-rel proto-oncogene product. Mol Cell Biol, 16(11), 5974-84, 1996 PMCID:231600

McKinsey, T A, Brockman, J A, Scherer, D C, Al-Murrani, S W, Green, P L, Ballard, D W. Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1: a potential mechanism for constitutive induction of NF-kappaB. Mol Cell Biol, 16(5), 2083-90, 1996 PMCID:231195

Scherer, D C, Brockman, J A, Bendall, H H, Zhang, G M, Ballard, D W, Oltz, E M. Corepression of RelA and c-rel inhibits immunoglobulin kappa gene transcription and rearrangement in precursor B lymphocytes. Immunity, 5(6), 563-74, 1996

Brockman, J A, Scherer, D C, McKinsey, T A, Hall, S M, Qi, X, Lee, W Y, Ballard, D W. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol, 15(5), 2809-18, 1995 PMCID:230512

Chen, Z., Hagler, J., Palombella, V., Melandri, F., Scherer, D., Ballard, D., and Maniatis, T. Signal-induced site- specific phosphorylation targets IkBa to the ubiquitin-proteasome pathway. Genes Dev., 9:(1586), 1995

Donald, R, Ballard, D W, Hawiger, J. Proteolytic processing of NF-kappa B/I kappa B in human monocytes. ATP-dependent induction by pro-inflammatory mediators. J Biol Chem, 270(1), 9-12, 1995

Scherer, D C, Brockman, J A, Chen, Z, Maniatis, T, Ballard, D W. Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. Proc Natl Acad Sci U S A, 92(24), 11259-63, 1995 PMCID:40611

Beraud, C., Sun, S., Ganchi, P., Ballard, D., and Greene, W. Human T-cell leukemia virus type I tax associat s with and is negatively regulated by the NF-kB2 p100 gene product: implications for viral latency. Mol. Cell Biol. , 14:(1374), 1994

Doerre, S., Sista, P., Ballard, D., and Greene, W. The c-rel proto-oncogene product represses NF-kB p65- mediated transcriptional activation of the HIV-1 long terminal repeat. Proc. Natl. Acad. Sci. USA , 90:(1023), 1993

Ganchi, P., Sun, S., Greene, W., and Ballard, D. A novel NF-kB complex containing p65 homodimers: implications for transcriptional control at the level of subunit dimerization. Mol. Cell. Biol. , 13:(7826), 1993

Sun, S., Ganchi, P., Ballard, D., and Greene, W. NF-kB controls expression of inhibitor Ik-Ba: evidence for an inducible autoregulatory pathway. Science , 259:(1912), 1993

Ballard, D., Dixon, E., Peffer, N., Bogerd, H., Doerre, S., and Greene, W. The 65-kD DNA binding subunit of human NF-kB functions as a potent transcriptional activator and a target for repression by the v-Rel oncoprotein. , 89:(1875), 1992

Ganchi, P., Sun, S., Greene, W., and Ballard, D. IkB/MAD-3 masks the nuclear localization signal of NF-kB and requires the transactivation domain to inhibit NF-kB p65 DNA binding . Mol. Biol. Cell , 3:(1339), 1992

Walker, W., Stein, B., Ganchi, P., Hoffman, J., Kaufman, P., Ballard, D., Hannink, M., and Greene, W. The v-rel oncogene: insights into the mechanism of transcriptional activation, repression, and transformation. J. Virol. , 66:(5018), 1992


Postdoctoral Position Available
Yes

Postdoctoral Position Details
A postdoctoral position is immediately available to study regulatory posttranslational modifications involved in immunoreceptor signaling to transcription factor NF-kB and MAP kinases. Qualifications include a Ph.D., M.D., or the equivalent, a strong publication record in the biomedical sciences, and prior experience with protein/nucleic acid biochemical techniques (eg., immunoprecipitation, immunoblotting, RNA/DNA blotting), gene targeting vectors, and phenotypic analyses of the immune system in mutant mice (eg., FACS, cell proliferation, apoptosis assays). For consideration, please send a current CV and three letters of recommendation from past and/or present training mentors to dean.ballard@vanderbilt.edu.

Updated Date
04/03/2009