Investigating the structure and mechanism of beta-catenin dependent gene transcription

Transcription regulators are proteins that control the rate at which DNA is read to make proteins, which carry out specific roles in the body. beta-catenin is a particularly important transcription regulator that is essential for proper cell growth, development and survival. Mutations that influence the ability of beta-catenin to carry out its function are associated with a wide variety of cancers, but most notably in skin and colon cancer. Blocking beta-catenin activity makes these cancer cells more susceptible to chemotherapies and can cause tumor regression. In order to carry out its activity, preliminary studies suggest that beta-catenin associates with another protein named CREB-binding protein (CBP), making this interaction a potential drug target. Despite the therapeutic potential of controlling beta-catenin function, the specific details of how beta-catenin associates with CBP still remains unclear. This research aims to understand both the biological function and mechanistic details of how these proteins interact with one another. I will first determine the atomic-resolution molecular structure of beta-catenin bound to CBP and probe where and how tightly they bind. Using this knowledge, I will then design molecules to disrupt these interactions and examine the biological effects in melanoma and colon cancer cell lines. This multidisciplinary project will help us understand the fundamental molecular mechanisms of gene regulation and may provide new targeted strategies to treat cancer.