PWD/Ph-encoded genetic variants suppress ApcMin-triggered intestinal tumor formation by modulating the cellular Wnt/beta-Catenin response
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE148370 | GEO | 2023/03/20
REPOSITORIES: GEO
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Project description:PWD/Ph-encoded genetic variants suppress ApcMin-triggered intestinal tumor formation by modulating the cellular Wnt/beta-Catenin response
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Project description:Aberrant activation of the Wnt/β-catenin signaling pathway has been observed in a wide range of human tumors. Deregulation of the pathway is closely linked to various aspects of human carcinogenesis such as cell viability, regulation of cell cycle, epithelial-mesenchymal transition, and maintenance of stemness. In addition, recent studies have disclosed the involvement of Wnt signaling in immune evasion of tumor cells. The accumulation of β-catenin in the nucleus is a common feature of cancer cells carrying defects in the pathway, which leads to the continuous activation of T-cell factor (TCF)/LEF transcription factors. Consequently, a genetic program is switched on, leading to the uncontrolled growth, prolonged survival, and acquisition of mesenchymal phenotype. As β-catenin/TCF serves as a signaling hub for the pathway, β-catenin/TCF-dependent transcriptional activity is a relevant readout of the pathway. To date, a wide variety of synthetic TCF/LEF reporters has been developed, and high-throughput screening (HTS) using these reporters has made significant contributions to the discovery of Wnt inhibitors. Indeed, HTS led to the identification of chemical probes targeting porcupine, a membrane bound O-acyltransferase, and CREB-binding protein, a transcriptional coactivator. This review focuses on various screening strategies for the discovery of Wnt inhibitors and their mode of action to help the creation of new concepts for assay/screening methods.
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Project description:Primary cilia act as crucial regulators of embryo development and tissue homeostasis. They are instrumental for modulation of several signaling pathways, including Hedgehog, WNT, and TGF-?. However, gaps exist in our understanding of how cilia formation and function is regulated. Recent work has implicated WNT/?-catenin signaling pathway in the regulation of ciliogenesis, yet the results are conflicting. One model suggests that WNT/?-catenin signaling negatively regulates cilia formation, possibly via effects on cell cycle. In contrast, second model proposes a positive role of WNT/?-catenin signaling on cilia formation, mediated by the re-arrangement of centriolar satellites in response to phosphorylation of the key component of WNT/?-catenin pathway, ?-catenin. To clarify these discrepancies, we investigated possible regulation of primary cilia by the WNT/?-catenin pathway in cell lines (RPE-1, NIH3T3, and HEK293) commonly used to study ciliogenesis. We used WNT3a to activate or LGK974 to block the pathway, and examined initiation of ciliogenesis, cilium length, and percentage of ciliated cells. We show that the treatment by WNT3a has no- or lesser inhibitory effect on cilia formation. Importantly, the inhibition of secretion of endogenous WNT ligands using LGK974 blocks WNT signaling but does not affect ciliogenesis. Finally, using knock-out cells for key WNT pathway components, namely DVL1/2/3, LRP5/6, or AXIN1/2 we show that neither activation nor deactivation of the WNT/?-catenin pathway affects the process of ciliogenesis. These results suggest that WNT/?-catenin-mediated signaling is not generally required for efficient cilia formation. In fact, activation of the WNT/?-catenin pathway in some systems seems to moderately suppress ciliogenesis.
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