Grant: $191,800 - National Institutes of Health - Aug. 27, 2009
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Award Description: The purpose of this research is to identify a novel signaling pathway down stream of epithelial basolateral junctions that suppresses invasion and metastasis. Epithelial-mesenchyme transition and cell invasion are crucial processes in tumor progression and metastasis. Systematic analysis of epithelial junction proteins in Drosophila has shown that while proteins of the Tight and Adherens junctions are important for repressing EMT, only proteins of the Basolateral junction also cause epithelial cells to become highly invasive. Four proteins that localize to the BLJ form an invasion-repressing complex that signals through Warts kinase to nuclear transcription factor Yorkie to repress invasion. Our data indicate that the Yap, the human homolog of the Yorkie transcription factor, plays similar roles in human ovarian epithelial cells. Because Yap is the most down stream component in the pathway, and is regulated by phosphorylation and nuclear localization, it provides several useful assays for establishing if the Basolateral junction signaling pathway that we pieced together in flies also represses tumor progression and metastasis in human ovarian epithelial cells. The purpose of this supplement request is to accelerate the pace of discovering the role of each component of the Basolateral junction signaling pathway in repressing carcinogenesis and invasion of human ovarian epithelial cells. Our plan is to obtain knock down and gain of function for each component of the pathway in human immortalized ovarian epithelial cells and then: (1) Determine which Basolateral junction proteins are required for Yap phosphorylation and nuclear localization, (2) Determine which Basolateral junction proteins are required for repressing ovarian epithelial cell carcinogenesis, and (3) Determine if Yap is required for expression of the Basolateral junction tumor suppressor phenotype. This will enable us to complete Aim 3c of the parent grant: Examine the function of invasion proteins in human breast and ovarian cancers. This aim was deemed by the reviewers of the parent grant to be most crucial goal that we needed to complete. We will thus delineate the first pathway by which Basolateral junctions control epithelial tumor progression and invasion, which may provide important tools for diagnosis and treatment of ovarian and other invasive epithelial cancers.
Project Description: As defined in the Award Description field
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 27, 2009. Help expand these official descriptions using the wiki below.