Figure 3
From: Interactive Toxicogenomics: Gene set discovery, clustering and analysis in Toxygates
Hypothetical model of the hepatotoxicity caused by WY-14643. Genes in M4vs8_cluster1 were upregulated predominantly in M24hr and M4. This results in elevated sensitivity of beta-catenin independent Wnt signaling and induction of Ca2+ pathway-related genes, followed by decreasing intracellular Ca2+ and Ca2+ release from ER in M4. Upregulation of genes in M4vs8_cluster3, which were also upregulated by amlodipine, implies the Ca2+ dynamics dysregulation in M4. Also, temporary upregulation of genes in M4vs8_cluster2 in M4 implies UPR response, which is a survival signalling from ER stress that can be caused by Ca2+ depletion at ER31. By long-term treatment of WY-14643 (M8, M15, M29), upregulation of genes in M4vs8_cluster1 (enriched pathways: “beta-catenin independent Wnt signalling”) and downregulation of genes in M4vs8_cluster 2 (enriched IPCs: “Protein processing in ER”) were observed. Since beta-catenin dependent Wnt signaling directly regulates cell cycle32 and beta-catenin independent Wnt signalling (non-canonical Wnt signalling, which is represented as “nc-Wnt signal” in Fig. 3) antagonises beta-catenin dependent Wnt signalling33, 34, it is implied that WY-14643 disrupts proper cell cycle regulation by inducing genes in beta-catenin independent Wnt signaling, while causing organelle proliferation by persistently activating PPARα signalling. The high-resolution image file is available at Scientific Reports online.
