Wnt signaling is one of the most common pathways linked to carcinogenesis in the intestine. The transcription factors that mediate Wnt signals are members of the Lymphoid Enhancer Factor/T Cell Factor (LEF/TCF) family. This four-member family is complex in that there are full-length activating forms, truncated dominant negative forms, and alternatively spliced isoforms that modify Wnt target gene recognition. TCF-1 and TCF-4 are the two family members expressed in the epithelial crypt compartment of the intestine. Normally, TCF-1 is expressed as a dominant negative isoform and it counteracts the action of TCF-4 which is expressed as a Wnt-mediating, active isoform. This pattern changes in cancer because TCF-1 expression switches to a full-length, Wnt mediating form. We have discovered a second DNA binding domain in TCF-1 and TCF-4 isoforms called the C-clamp. We have shown that the C-clamp is important for regulating cell proliferation of colon cancer cells. We have also identified Wnts that trigger TCF-1 export in colon cancer cells. Export of TCF-1 leaves the C-clamp form of TCF-4 in the nucleus to mediate aberrant Wnt signaling.
Three aims are proposed for this project. First, the extracellular Wnts and intracellular components that direct TCF-1 nuclear export will be defined (Aim1). Second, the biological impact of export will be defined in colon cancer cells and colon cancer initiating 3D cultures (Aim2). Third, the DNA binding specificities and target gene selection of C-clamp forms of TCF-1 and TCF-4 will be defined through genome-wide binding assays (ChIP-Seq), high-throughput protein binding microarrays, and in vitro biochemical analysis (Aim3). The overall goal is to define the mechanisms behind changes in TCF expression in colon carcinogenesis, and to define how extracellular Wnts and DNA binding specificities of TCFs influence aberrant signaling in colon cancer cells with stabilized ?-catenin.
In colon cancer, Wnt signaling is an overactive and strong signal for tumor initiation and progression. Wnt signaling is mediated by the TCF transcription factors and we have discovered their activities and expression to be different in colon cancer versus normal colon tissue. This project investigates basic mechanisms of TCF localization and gene targeting and asks how differences in these attributes contribute to the cancer cell phenotype.
| Lee, Mary; Chen, George T; Puttock, Eric et al. (2017) Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer. Mol Syst Biol 13:912 |
| Lyou, Yung; Habowski, Amber N; Chen, George T et al. (2017) Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy. Br J Pharmacol 174:4589-4599 |
| Sprowl-Tanio, Stephanie; Habowski, Amber N; Pate, Kira T et al. (2016) Lactate/pyruvate transporter MCT-1 is a direct Wnt target that confers sensitivity to 3-bromopyruvate in colon cancer. Cancer Metab 4:20 |
| Chen, George T; Waterman, Marian L (2015) Cancer: leaping the E-cadherin hurdle. EMBO J 34:2307-9 |
| Vuong, Linh M; Chellappa, Karthikeyani; Dhahbi, Joseph M et al. (2015) Differential Effects of Hepatocyte Nuclear Factor 4? Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells. Mol Cell Biol 35:3471-90 |
| MacDonald, Bryan T; Hien, Annie; Zhang, Xinjun et al. (2014) Disulfide bond requirements for active Wnt ligands. J Biol Chem 289:18122-36 |
| Ehsan, Seema M; Welch-Reardon, Katrina M; Waterman, Marian L et al. (2014) A three-dimensional in vitro model of tumor cell intravasation. Integr Biol (Camb) 6:603-10 |
| Hoverter, Nate P; Zeller, Michael D; McQuade, Miriam M et al. (2014) The TCF C-clamp DNA binding domain expands the Wnt transcriptome via alternative target recognition. Nucleic Acids Res 42:13615-32 |
| Pate, Kira T; Stringari, Chiara; Sprowl-Tanio, Stephanie et al. (2014) Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J 33:1454-73 |
| Chodaparambil, Jayanth V; Pate, Kira T; Hepler, Margretta R D et al. (2014) Molecular functions of the TLE tetramerization domain in Wnt target gene repression. EMBO J 33:719-31 |
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