COBRE: USC: APC AND MITOSIS - LINK WITH CYTOPLASMIC DYNEIN, COLON CANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. APC mutations cause colorectal tumors in humans and intestinal tumors in the Min mouse. The APC-binding proteins EB1 and beta-catenin have been linked to DYNC1, a microtubule motor, suggesting DYNC1 function may be important in tumorigenesis. In a project mainly covered by COBRE funding, we found that Lis1, which is best known for it¿s role in neuronal migration, stimulates the enzymatic activity of brain DYNC1 in vitro (J. Neurosci. February 2006, 26 8). More recent work demonstrates that Lis1 is a universal DYNC1 activator, and is a likely target of regulatory pathways (submitted to JCB). The Min mutation impacts DYNC1 distribution, and Lis1expression impacts EB1 behavior, so changes in DYNC1 activity could impact tumor formation in Min mice. To test this, Min mice are being crossed to mice carrying a null Lis1 allele. By 9 weeks, the third generation double Lis1/Min mutants (87.5% genetic background of standard Min mice) averaged 2.3 tumors in the duodenum (n=21) compared to 9.8 tumors in littermates with only the Min mutation (n=28). This was not observed in other parts of the gut. Enterocyte progression along the crypt-villus axis is delayed in Lis1+/- mice; the fact that duodenal villi are very long may account for the sensitivity of this region to Lis1 mutations. Future studies will map and characterize functional interactions between DYNC1 and APC pathways. In another project, we have discovered intriguing cytoskeletal changes induced by PPAR-? agonists. These drugs may be chemopreventive/anticarcinogenic, depending on APC status. We are determining how APC mutations affect cytoskeletal changes induced by PPAR-gamma agonists. Dr. Smith has graduated from COBRE funding, so that this project will not be included as a Research Subproject in the next year.