Phase II year
1997
(last award dollars: 1998)
The APC gene is mutated in almost all colon cancers, which rank second as a cause of cancer related mortality. APC has been placed in a signaling pathway involving its regulation of beta-catenin, a protein now known to activate transcription. Abnormal accumulation of beta-catenin is observed in cancer cells mutant for APC and preliminary evidence indicates that specific mutants of beta-catenin, which exhibit abnormal protein stability, exist in other cancers. A systematic search for relevant beta-catenin mutants in a wide range of cancers will be initiated. Research efforts will focus on the elucidation of beta-catenin' potential interaction with the LEF/TCF family of transcription enhancers in cancer. Specific transcriptional enhancers associated with beta- catenin will be identified and their ability to mediate beta-catenin dependent transactivation will be tested. The effects of dominant negative mutants of the LEF/TCs on tumorigenicity will also be examined. Target genes activated by stabilized beta-catenin mutants will be determined using conditional expression and differential display methodologies. An assay employing transactivation by LEF-beta-catenin of a promotor driving luciferase expression will be developed for the purposes of high throughput screens that identify compounds having a negative effect on beta-catenin-dependent transactivation.Proposed commercial application:Deregulation of beta-catenin represents a new cancer pathway which can be exploited for the purposes of targeted therapeutic intervention. New chemotherapeutics can be identified in drug screens employing components from this pathway.Thesaurus termsactin binding protein, adenomatous polyp, genetic transcription, neoplasm /cancer genetics, tumor suppressor protein cell adhesion molecule, colorectal neoplasm, gene deletion mutation, molecular oncology, nucleic acid sequence, oncogene, protein kinase, protooncogene enzyme linked immunosorbent assay, molecular cloning, northern blotting, reporter gene, tissue /cell culture, western blottingNational Cancer Institute (NCI)
