Our Lab studies the molecular mechanism by which NF-kB produces lymphomagenesis, focusing on protein interactions and the identification of NF-kB depedent genes that contribute to pathologic lymphoid formation. Constitutive activation of NF-kB has been implicated in tumorigenesis of several lymphoid malignancies such as Non-hodgkin's, Hodgkin Lymphoma, and multiple myeloma. For this reason the NFkB pathway is an attractive therapeutic target to be explored.

The NF-kB pathways include the ‘‘canonical'' (classical) and ‘‘noncanonical'' (alternative) pathways using NF-kB precursor proteins, p105 (NF-kB1) and p100 (NF-kB2), respectively. During activation, these proteins are processed to mature p50/ NF-kB1 and p52/NF-kB2 proteins that heterodimerize with other members of the NF-kB family, p65/Rel-A or c-Rel, or Rel-B, respectively. Activation of the canonical pathway involves release of p50–p65 from IkB after IkB is phosphorylated by IkB kinase (IKK) and degradated by the proteasome. Activation of the noncanonical pathway involves cleavage of p100 and dimerization of the mature p52 product with Rel-B. Most of the knowledge in this field has demonstrated that activation of the canonical pathway promotes cancer cell proliferation, prevents apoptosis, and increases angiogenic and metastatic potential. In our lab we found that these properties hold true for the non-canonical pathway as well, but the mechanism responsible for these effects differed between the two pathways.

We are currently investigating p100 and p105 in relation to activation of apoptosis using a proteomic approach to identify multi-protein complexes required for activation of the caspase cascade. We are also discovering novel downstream targets responsible for the tumorigenic effect of NFkB using gene expression analysis and sirna techniques. Our long-term goal is to define the mechanisms responsible for switching the physiological signals of NFkB to tumor promoting signals in lymphoid tissues. The results of this work will translate into the identification of novel targets that can be used for drug development or to predict response to specific therapies in lymphomas.

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