ADENOMATOUS POLYPOSIS COLI AND MITOSIS: A ROLE FOR CYTOPLASMIC DYNEIN

University Of South Carolina At Columbia, Columbia SC

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Abstract

Mutations in the adenomatous polyposis coli (APC) tumor suppressor protein are hallmarks of colorectal cancer. A large body of work has underscored APC's importance in regulating another protein, beta-catenin. Disruption of this role (a consequence of most APC mutations) contributes considerably to cancer development. Among other things, APC seems to be important for getting beta-catenin out of the nucleus and preventing over-stimulation of key genes. When APC cannot interact with beta-catenin, too much beta-catenin stays active in the nucleus. We are interested in learning how APC and beta-catenin get to the nucleus in the first place. One clue is that another tumor suppressor, p53, relies on a motor protein that can move along microtubules (cytoskeletal structures that serve as tracks) toward the nucleus. We hypothesize that the same motor, called cytoplasmic dynein, also transports APC and beta-catenin to the nucleus. Recent reports that beta-catenin interacts directly with dynein makes this even more likely. In addition to beta-eatenin deregulation, cells with defective APC have chromosome abnormalities. This probably arises through disruption of two APC interactions. First, APC normally binds to microtubules, which also function during the segregation of chromosomes into daughter cells during mitosis. Second, APC binds to EB 1, a kinetochore protein that interacts with dynein. We have found that EB 1 also interacts with two dynein-regulatory proteins, Lisl and Nudel. These proteins function during chromosome segregation and spindle orientation, as does cytoplasmic dynein. Based on this, we hypothesize that the interaction of APC with dynein and its regulatory proteins may play a pivotal role in these processes. Taken together, the accumulating data suggest the possibility that faulty interactions between APC and dynein motors could play a role in colorectal cancer. We have the following specific aims: 1. To study the extent of cytoplasmic dynein's involvement in the shuttling of APC/beta-catenin. 2. To further characterize and determine the significance EB 1/Lis 1/Nudel interactions . 3. To study dynein-based transport of transforming mutants of p53 and APC. The long-term goal of the proposed project is to understand how APC works and how mutant proteins contribute to colorectal cancer. Ultimately, these experiments could lead to the verification of new targets for chemothemputic agents.