Biology of the Myb-MuvB Oncoprotein Tumor Suppressor Protein Complex

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DESCRIPTION (provided by applicant): Cancer is caused by mutations (alterations) in oncogenes and tumor suppressor genes. Much of what we know about the function of cancer-causing genes comes from studies of genetic model organisms like fruit flies and soil nematodes. This project focuses on the Myb oncoprotein and its interactions with a four-protein tumor suppressor complex called the MuvB core. The fruit fly is an excellent model for these studies because it has only one Myb gene, whereas vertebrate animals including humans have three related Myb genes. In particular, the human B-Myb gene that is associated with poor prognosis in human breast cancer is structurally similar to and can functionally replace the Myb gene of fruit flies. Previous work has shown that the MuvB tumor suppressor proteins prevent the expression of genes that promote cell division. The Myb protein directly interacts with the MuvB proteins, thereby permitting the expression of the genes that MuvB inhibits. A major goal of this proposal is to understand in molecular detail the mechanism by which Myb and MuvB regulate gene expression. The tools of genetics, biochemistry, and cell biology will be used to identify the changes in chromatin (DNA and associated proteins) that occur in the presence of Myb and MuvB. Another major goal is to understand exactly how the Myb and MuvB proteins interact with and regulate one another. A relatively small portion of the Myb protein is sufficient to interact with the MuvB proteins and inhibit their function. A better understanding of the precise structures that mediate this interaction may lead to the development of new small molecules that will be useful in the treatment of breast cancers with increased levels of B-Myb.