Determination of molecular pathways regulating LOT1 mediated growth suppressions

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DESCRIPTION: (Applicant's Description) We previously reported discovery of the LOT1 (Lost On Transformation) gene (GenBank accession #U72620) through analysis of gene expression differences between normal and malignantly transformed rat ovarian surface epithelial (ROSE) cells, an in vitro ovarian cancer model. The gene frequently shows decreased or lost expression in independently transformed ROSE cell lines compared to the normal progenitor cells. Based on these observations, we considered the LOT1 gene a potential candidate gene involved in regulating human ovarian cancer. In an effort to translate this finding in a model system to human disease, we cloned the human homologue, LOT1 (GenBank accession #72621). Interestingly, the human gene maps to chromosome 6 at band 25 (6q25), which is a site for loss of heterozygosity (LOH) in ovarian cancer and many other solid tumors. Expression of the LOT1 gene was lost or decreased in seven out of eleven ovarian cancer cell lines consistent with the findings in the rat ovarian cancer cell lines. The deduced amino acid sequence of LOT1 indicates that it is a zinc-finger motif containing protein with domains characteristic of transcription factors. Functional assays proved that it is a nuclear protein with a potential role as a transcription factor. We also found that the LOT1 gene is involved in the epidermal growth factor receptor (EGFR) signaling pathway and is a negative regulator of the ovarian cancer cell growth. The goal of this proposal is to further ascertain the clinical importance of LOT1 by determining how down-regulation or lost expression/function of LOT1 transduces anti-proliferative signals and behaves as a tumor/growth suppresser gene regulating other genes, which inhibit the malignant phenotype. To elaborate these mechanisms we will investigate the upstream regulators and downstream events associated with the action of the LOT protein and to determine how these normal processes are perturbed in ovarian malignancies. Hopefully, these endeavors will result in a better understanding of the ovarian cancer development and/or progression and provide a basis for more effective diagnosis, treatment, and/or management of the disease.