GSK3 and Cancer

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Many of the components of the Wnt signaling pathway are over-expressed or mutated in different tumors [38]. For example, virtually all colon tumors arise from an initiating mutation in the APC gene (85%) or in the P-catenin gene (10-15%) that makes P-catenin resistant to degradation. Axin mutations occur in hepatocellular carcinomas and FRAT1 in T-cell lymphomas. Alterations in these components would be predicted to lead to inappropriate accumulation of P-catenin.

These observations have implications for the development of GSK3 inhibitors to treat diabetes and other diseases, as compounds that target the ATP-binding site, such as SB 216763 and SB 415286, inhibit the phosphorylation of all GSK3 substrates, including Axin and P-catenin. They therefore mimic the Wnt signaling pathway and stimulate the accumulation of P-catenin [32]. The development of GSK3 inhibitors that do not have the potential to be oncogenic may therefore require the identification of compounds that prevent the phosphorylation of glycogen synthase but which do not inhibit the phosphorylation of Axin and P-catenin. This may be possible because Axin and P-catenin appear to bind to GSK3 at sites distinct from glycogen synthase and eIF2B. Mutations in GSK3 have been identified that prevent the phosphorylation of glycogen synthase and eIF2B but not the phosphorylation of Axin and P-catenin, and vice versa [14, 39].


Our research on GSK3 is supported by the U.K. Medical Research Council, The Royal Society, Diabetes U.K., AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novo Nordisk and Pfizer.


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