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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center


Dean W. Ballard, Ph.D.

Professor of Pathology, Microbiology and Immunology

Contact Information:

Vanderbilt University Medical Center
813 Light Hall
Nashville, TN 37232

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.