SORAB'S LABORATORY


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One of the most common causes of death in patients suffering from epithelial tumors is metastasis and the formation of secondary tumors. A primary requirement for the initiation of metastasis is the dissolution of cell-cell contacts in the tumor tissue, followed by the cells entering the blood stream. Epithelial cells contain multiple cell-cell junctions that regulate tissue morphogenesis and also allow communication between different cells in a tissue. One major junction that is required for epithelial cell function is the desmosome and loss of desmosomal proteins is often observed in metastasizing tumor cells. Our work has demonstrated that the initiation of desmosome formation is dependent on the plaque protein, plakophilin3, in human cells. Loss of plakophilin3 leads to increased neoplastic progression and metastasis and our work has identified molecular determinants downstream of plakophilin3 loss that are important for tumor progression and metastasis. Studying the mechanisms by which cell-cell interactions are generated and dissolved will lead to an understanding of the molecular mechanisms by which these processes are regulated and may lead to the development of novel therapeutic strategies for treating neoplastic disease.

Another area of focus in the laboratory is to elucidate the mechanisms by which the 14-3-3 protein family regulates different cellular processes. As part of these studies we have determined the molecular basis for specific complex formation between 14-3-3 proteins and the cdc25C protein phosphatase. Our work has demonstrated that loss of two 14-3-3 isoforms, 14-3-3ε and 14-3-3γ has resulted in override of both the S-phase and G2 DNA damage checkpoints resulting in cell death. A conserved structural fold present in these two 14-3-3 proteins allows them to form a specific complex with and inhibit cdc25C function in vivo and disruption of this complex can lead to inhibition of tumor growth. These studies have been extended to identify specific ligands for individual 14-3-3 isoforms to determine how individual family members regulate different cellular pathways.

Finally, another area of work in the laboratory has focused on devising novel technologies for the generation of transgenic mice that either over-express or have a knockdown of specific gene products.