Ph.D. Student
Vanderbilt University Medical Center
Department of Cell & Developmental Biology
Email: curtis.thorne@vanderbilt.edu
Dallas, TX
B.S. Biology
Baylor University, Waco, TX 2000
Thorne, C. and A. V. Lee (2003). "Cross talk between estrogen receptor and IGF signaling in normal mammary gland development and breast cancer." Breast Dis 17: 105-14.
Wnt/β-catenin signaling is essential for proper development and is misregulated in human cancers. My project begins with the hypothesis that Wnt mediated axin degradation is critical for pathway activation. A small molecule which blocks axin degradation would potently drive down -catenin concentrations and prevent signaling. Utilizing in vitro reconstitution in Xenopus egg extracts, I have conducted a forward chemical genetic screen of the Wnt pathway. Addition of β-catenin-firefly luciferase and axin-Renilla luciferase fusion proteins to Xenopus extracts allowed me to simultaneously screen chemical libraries for regulators of β-catenin and axin turnover. A number of "hits" have been identified and validated in Xenopus embryos and cell culture secondary assays. One hit, WS30, is a particularly potent Wnt inhibitor with an EC50 of ~10nM. Studies in mammalian cell culture have shown that WS30 greatly slows the rate of axin turnover and decreases cytoplasmic β-catenin. Concordantly, Wnt target genes are down-regulated by WS30 at both the mRNA and protein level. In vivo studies in Xenopus embryos have shown that WS30 can reverse both Wnt8 mediated secondary axis formation and activation of Wnt target genes, siamois and xnr3. Utilizing affinity purification methods, I am now working to identify the direct molecular target of WS30. Pharmacologic inhibitors of Wnt signaling would be valuable tools for studying the Wnt pathway during development and may be useful for perturbing Wnt signaling in certain disease states.