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Regulation of tumor progression by 14-3-3 proteins

Plakophilin3 (PKP3) is a desmosomal plaque protein that is required for desmosome formation and whose levels are decreased in multiple tumor types, especially in de-differentiated and metastatic tumors. Our results have demonstrated that loss of PKP3 leads to defects in desmosome formation that are accompanied by a decrease in cell-cell adhesion and an increase in migration and invasion, all features of metastatic tumor cells. Indeed, PKP3 loss led to an increase in tumor formation in immunocompromised mice and an increase in metastatic progression. Further work identified various molecules whose expression was altered upon PKP3 loss. Our work has demonstrated that PKP3 loss leads to an increase in the protein levels of the Phosphatase of Regenerating Liver-3 (PRL-3), which is often over-expressed in metastatic tumors. The increase in PRL-3 levels leads to an increase in the levels of Keratin-8 (K8) and Matrix Metalloproteinase-7 (MMP7) and both of these are required for the increased tumor formation and metastasis observed upon PKP3 loss. In addition to these findings, our work also demonstrates that PKP3 loss leads to an increase in the levels of Lipocalin2 (LCN2), a protein required for iron uptake in cells. Loss of LCN2 leads to a decrease in the tumor progression and metastasis observed upon PKP3 loss. One goal of the laboratory is to identify mechanisms leading to tumor progression and metastasis in the hope that this will result in the identification of novel therapeutic targets for the treatment of metastatic disease. In addition, we wish to extend our observations obtained from our work in human cell lines to develop mouse models that mimic human disease. We would specifically like to develop a tissue specific knockout of plakophilin3 in the colon and determine if it could lead to metastatic progression in mice that have developed a primary tumor in the colon. If successful, these experiments will validate our cell line based assays and will provide us with an in vivo model that could be used to identify drugs that target metastatic disease.

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