Paul J. Galardy, M.D.

My research interests are focused on the involvement of the ubiquitin-proteasome system in the pathogenesis of cancer.

Ubiquitin (Ub), a small highly conserved protein, is attached to proteins in order to change their function, localization, or to direct them to the proteasome for degradation. The specificity of Ub attachment is regulated by two large enzyme families called ubiquitin ligases and de-ubiquitinating enzymes (DUBs); with ligases responsible for attachment and DUBs catalyzing the removal of Ub. Many critical cellular events are under the control of this system, including those of cell division. It is therefore not surprising that a growing list of human cancers is associated with deregulated activity of these enzymes. My interests focus on the involvement of DUBs in the development of cancer.

Specific Research Topics

De-Ubiquitination and T-cells

Interleukin-2 (IL-2) is a powerful signal for the growth of T-lymphocytes and is involved in promoting the growth of some forms of T-cell lymphoma. Following the binding of IL-2 to its receptor on the surface of T-cells, a series of phosphorylation events, involving several protein intermediates, transmit this signal to the cell nucleus in order to affect gene expression. While it is appreciated that several of these signaling intermediates are controlled in part by timed destruction through the ubiquitin-proteasome system, little is known about how these events are regulated.

The de-ubiquitinating enzyme DUB-2 is rapidly induced in T-cells following exposure to IL-2. Work from others has demonstrated that DUB-2 expression leads to enhanced IL-2 signaling and resistance to apoptosis, though the molecular basis for these effects are not currently understood.

I am currently working on in vitro and in vivo systems in order to determine the role of DUB-2 in T-cell growth and development. These experiments will lead to an improved understanding of what DUB-2 is doing in IL-2 stimulated T-cells, and will lead to an improved molecular understanding of the role of Ub in this process.

The Role of De-Ubiquitination in the Development of Burkitt Lymphoma

Using novel activity-based probes which detect active DUBs, we are developing activity signatures of DUBs in human cancer which may aid in the identification of cancer-related DUBs. Using this methodology we identified the enzyme UCH-L1 as highly active in several forms of human B-cell malignancies including Burkitt lymphoma. This enzyme has further been implicated in several other forms of cancer including that of the lung, colon, pancreas, esophagus, thyroid and others. The cellular function of UCH-L1 is poorly understood. The role of UCH-L1 in lymphoma development is being explored through the development of mouse models and through the exploitation of small molecule inhibitors of UCH-L1 activity. The results of this work may lead to the development of novel pharmacologic agents for the treatment lymphoma and perhaps other forms of B-lymphocyte cancer.