Primary interests include Cancer; Oncogenes; Tumor Suppressor; Genes Programmed Cell Death (apoptosis); Chemoresistance, and Angiogenesis

One focus of my research is the p53 gene, which is mutated in one-half of human cancer. Defects in the p53 signaling pathway very likely may encompass most of human cancer. The p53 gene plays roles in the repair of damaged DNA, regulation of the cell cycle, tumor suppression, and apoptosis (programmed cell death). The p53 protein functions as a transcription factor and regulates the expression of many different types of genes involved in cell growth, death, and cancer. I have targeted my studies on a novel p53-induced gene, proline oxidase, which plays a role in p53-dependent apoptosis. Proline oxidase is a mitochondrial enzyme that is a central player in the proline redox cycle. Renal carcinomas have defects in the expression of both proline oxidase and p53, implicating proline oxidase as a p53-downstream player in the development of renal carcinomas. Proline oxidase mediates the p53-dependent activation of calcineurin, a protein phosphatase, during apoptosis. Our future goals are to understand how the calcineurin pathway activates apoptosis and how defects in this pathway are related to renal carcinoma.

A second area of interest is the mechanisms of evolution of chemoresistance in diffuse large B-cell lymphoma (DLBCL). The CHOPS drug regimen (doxorubicin/ cyclophosphamide/vincrinstine/prednisone) is currently the most effective treatment for DLBCL patients. Unfortunately, about one-half of DLBCL patients develop drug resistance leading to high mortality. As a model system, we generated CHOP-resistant DLBCL cell lines through repeated selections in the presence of CHOP. We have been using proteomics to investigate differences in protein expression between the CHOP-sensitive and –resistant DLBCL cells. One target of interest has been identified as the 14-3-3zeta protein, a known prosurvival gene product. CHOP-resistant cells overexpressed the 14-3-3zeta protein leading us to hypothesize that it might provide DLBCL cells with the selective advantage to survive CHOP treatment. Studies are underway to investigate the role of 14-3-3 in the development of CHOP resistance in DLBCL.