Targeting of Oncogenic Proteins for Intracellular Degradation

摘要

Beta-catanin, is an important component of the wnt signaling pathway and IkBalpha is an important regulator of the NF-KB pathway. Both proteins are phosphorylated at serines in the N- terminal region, which subseouently target them for ubiquitination by the same ubiquitin ligase complex. In the first year of the award, we demonstrated proof of principle that small peptides could be constructed that would enter cells and target oncogenic proteins, such as beta- catenin and erbB2 for intracellular degradation. During the course of this work, we discovered that he similarities in the regulation of beta-catenin and IkBalpha ubiquitination extended to the kinases that are involved in control of their phosphorylation. The IKK complex is responsible for the phosphorylation of IkBalpha while GSK-3beta is thought to regulate beta-catenin phosyphorylation. This work showed for the first time that IKK also exists in a complex with beta- catenin and that expression of either IKKalpha or IKKbeta can decrease beta- catenin signaling. Consistent with this, we found that cytokines, such as TNFalpha also markedly regulated beta-catenin activity. Our demonstration that cytokine and beta-catenin signaling are cross-regulated at the level of targeted protein degradation is important and points to a clinically significant relationship between inflammatory responses and oncogenic activity.