Chemical Disruption of Wnt Signaling and Telomere Length Maintenance



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A nearly universal feature of colorectal cancer (CRC) incidents is the presence of genetic alterations that promote deviant activation of the TCF/LEF transcriptional regulators. The TCF/LEF proteins control the transcriptional output of intercellular signaling mediated by the Wnt family of secreted ligands. Several chemical screening efforts devoted to disrupting deviant TCF/LEF activity have converged on two vulnerabilities in the Wnt pathway -- the poly-ADP-ribose polymerases, Tankyrase 1 and 2 (Tnks1 and 2) that control the threshold response levels to Wnt ligands, and the Wnt acyltransferase Porcupine that provides an essential fatty acyl adduct to all nineteen Wnt ligands. My thesis focuses on the chemical biology of one of these strategies -- the Tnks enzymes -- with the goal of understanding the strengths and limitations of drugging the Tnks proteins for achieving therapeutic goals in regenerative medicine and cancer. Given the previously assigned role of Tnks enzymes in telomere maintenance, I have also devoted considerable effort to understanding the cell biological effects of disrupting Tnks activity on telomere integrity. Finally, I mined a high-confidence collection of Wnt pathway inhibitors with previously unidentified mechanisms of action to identify novel small molecules that directly target the TCF/LEF transcriptional apparatus. This effort netted a chemical approach for disabling deviant transcriptional activity in CRC that is distinct from the one afforded by Tnks and Porcn inhibitors. Taken together, my thesis establishes a chemical toolkit for interrogating the inner workings of Wnt-mediated signaling and also reveals new avenues for disabling deviant Wnt responses in cancer and normal Wnt responses in tissue engineering.

General Notes

Pages xvii-xviii of the dissertation are incorrectly numbered as pages xvi-xvii.

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