CRYSTALLOGRAPHIC STUDIES OF BETA CATENIN AND LEF/TCF

Stanford University, Stanford CA

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Abstract

Regulation of transcription is vital for controlled cellular growth. Disruption or overproduction of transcriptional activators or repressors oftentimes results in uncontrolled tumorogenic growth. Regulation of a complex formed by the proteins beta-catenin and members of the Lef/Tcf family, downstream components of the Wnt/Wg signaling pathway that controls cell fate determination in early embryogenesis, is an example of this phenomenon. Upon Wnt/Wg signaling this complex forms and moves to the nucleus, binds DNA, and activates transcription of target genes. In several transformed cell types, defects in beta-catenin turnover lead to large amounts of this complex in the nucleus. Lef/Tcf family members are architectural transcription factors that introduce a large bend in DNA. Binding of beta-catenin to Lef/Tcf proteins drastically reduces DNA bending and is associated with the activation of genes in the Wnt/Wg pathway. Three-dimensional structural data of a beta-catenin/Lef or Tcf binary complex or ternary complex containing DNA are necessary to understand how these proteins synergistically function as co-activators of transcription, and also how the role of post-translational modifications can affect these interactions. It is my intention to pursue X-ray crystallographic studies of these complexes to further structural understanding of the Wnt/Wg signaling pathway. This information will provide insight regarding the role this complex plays in the pathway of oncogenic transformation.