Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA317439 | ENA |
REPOSITORIES: ENA
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Project description:We have shown that β-catenin overexpression induced blockage of monocyte-macrophage differentiation by inhibiting PU.1-targeted gene transcription including Egr2 expression in myeloid progenitor cells. Our results suggest that compromised PU.1-targeted gene transcription induced by β-catenin overexpression, at least partially, may mediate a pathogenic role of β-catenin in myeloid leukemia.
2016-04-06 | GSE79932 | GEO
Project description:We have shown that β-catenin overexpression induced blockage of monocyte-macrophage differentiation by inhibiting PU.1-targeted gene transcription including Egr2 expression in myeloid progenitor cells. Our results suggest that compromised PU.1-targeted gene transcription induced by β-catenin overexpression, at least partially, may mediate a pathogenic role of β-catenin in myeloid leukemia. PUER cells were infected with retrovirus expressing beta-catenin-S33Y or control vector MIGR1. Five days after infection, the GFP positive cells were sorted by flow cytometry, and were treated with 4-OHT to induce the expression of PU.1. Total RNA was exacted from cell samples and purified by RNeasy Micro kit (Qiagen). cRNAs were generated and hybridized to the mouse whole genome 4Ã44K arrays according to manufacturerâs instructions (Agilent Technologies).
2016-04-06 | E-GEOD-79932 | biostudies-arrayexpress
Project description:SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes displace nucleosomes to promote the access of transcription factors to enhancers and promoters. Despite the critical roles of SWI/SNF in animal development and tumorigenesis, how signaling pathways recruit SWI/SNF complexes to their target genes is unclear. Here, we demonstrate that target gene activation mediated by Beta-catenin, the essential transcriptional coactivator in the Wnt signal transduction pathway, requires ubiquitylation of the SWI/SNF component Brahma-related gene-1 (BRG1) by the E3 ubiquitin ligase Thyroid Hormone Receptor Interactor 12 (TRIP12). TRIP12 depletion in Drosophila, zebrafish, mouse organoids, and human cells attenuates Wnt signaling. Genetic epistasis experiments place TRIP12 activity downstream of the Beta-catenin destruction complex. TRIP12 interacts with and ubiquitylates BRG1, and BRG1 depletion blocks TRIP12-mediated Wnt pathway activation. TRIP12 promotes BRG1 binding to Beta-catenin in the presence of Wnt. Our findings support a model in which TRIP12 ubiquitylates BRG1 in the presence of Wnt and promotes its interaction with Beta-catenin, thereby bringing SWI/SNF to Wnt target genes. Our studies suggest a general mechanism by which cell signaling induces the interaction between BRG1 and pathway-specific transcription factors to recruit SWI/SNF complexes to their appropriate target genes.
2024-01-06 | MSV000093784 | MassIVE
Project description:The mechanism by which Wnt signaling, an essential pathway controlling development and disease, stabilizes beta-Catenin has been a subject of debate over the last three decades. Casein kinase 1alpha (CK1a) functions as a pivotal negative regulator of this signaling pathway, initiating the events that destabilize beta-Catenin. However, whether and how CK1a activity is regulated in Wnt-off and Wnt-on states remains poorly understood. We now show that CK1a activity requires its association with the alpha catalytic subunit of Protein phosphatase 2A (PPP2CA) on AXIN, the scaffold protein of the beta-Catenin destruction complex. Wnt stimulation induces the dissociation of PPP2CA from CK1a, resulting in CK1a autophosphorylation and its consequent inactivation. Moreover, autophosphorylated CK1a is enriched in a subset of colorectal cancers (CRC) harboring constitutive Wnt activation. Our findings identify a novel mechanism by which Wnt stimulation inactivates CK1a, filling a critical gap in our understanding of Wnt signaling, with relevance for CRC.
| MSV000095904 | MassIVE
Project description:The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRC) resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex. USP7 depletion in APC-mutated CRC inhibits Wnt activation by restoring β-catenin ubiquitination, drives differentiation and suppresses xenograft tumor growth. Finally, the Wnt-activating role of USP7 is specific to APC mutations, thus can be used as tumor-specific therapeutic target for most CRCs.
2017-11-09 | PXD007947 | Pride
Project description:Because of its insensitivity to existing radiotherapy, namely chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/β-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated wnt/β-catenin pathway of TNBC tissues, lnc-WAL (wnt/β-catenin associated lncRNA; WAL) was selected as the top upregulated lncRNA in wnt/β-catenin pathway activation compared with the inactivation group. RIP-seq was used to compare the β-catenin and IgG groups, where lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted EMT, the proliferation, migration and invasion of breast cancer stem cells (BCSCs), and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via Axin-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/Axin/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC.
2025-05-24 | GSE268287 | GEO
Project description:Wnt/β-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating β-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment β-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy.
2019-08-31 | GSE136664 | GEO
Project description:To screen the associated lncRNAs with wnt/β-catenin pathway activation of TNBC,through lncRNA microarray profiling between activated and inactivated wnt/β-catenin pathway of TNBC tissues, lnc-WAL (wnt/β-catenin associated lncRNA; WAL) was selected as the top upregulated lncRNA in wnt/β-catenin pathway activation compared with the inactivation group.
2024-07-05 | GSE270306 | GEO
Project description:During mammalian kidney development, mesenchymal nephron progenitors (cap mesenchyme) differentiate into the epithelial cells that go on to form the nephron. Although differentiation of nephron progenitors is triggered by activation of Wnt/b-catenin signaling, constitutive activation of Wnt/b-catenin signaling blocks epithelialization of nephron progenitors. Full epithelialization of nephron progenitors requires transient activation of Wnt/b-catenin signaling. We performed transcriptional profiling of nephron progenitors responding to constitutive or transient activation of Wnt/b-catenin signaling.
2012-09-11 | GSE39583 | GEO
Project description:The WNT/β-catenin signaling pathway is evolutionarily conserved and controls normal embryonic development, adult tissue homeostasis, and regeneration. Aberrant activation or suppression of WNT signaling contributes to cancer initiation and progression, developmental disorders, neurodegeneration, and bone disease. Despite great need and more than 40 years of research, targeted therapies for the WNT pathway have yet to be fully realized. Kinases are exceptionally druggable and occupy key nodes within the WNT signaling network, but several pathway-relevant kinases remain understudied and ‘dark’. Here we studied the function of the CSNK1g subfamily of human kinases. miniTurbo-based proximity biotinylation and mass spectrometry analysis of CSNK1γ1, CSNK1γ2, and CSNK1γ3 revealed numerous established components of the β-catenin-dependent and independent WNT signaling pathways, as well as novel interactors. In gain-of-function experiments using a panel of transcriptional reporters, CSNK1γ3 but not CSNK1γ1 or CSNK1γ2 activated β-catenin-dependent WNT signaling, with minimal effect on other signaling pathways. Within the family, CSNK1γ3 expression uniquely induced LRP6 phosphorylation. Conversely, siRNA-mediated silencing of CSNK1γ3 alone had no impact on WNT signaling, though co-silencing of all three family members decreased WNT pathway activity. We characterized two moderately selective and potent small molecule inhibitors of the CSNK1γ family. These inhibitors and a CSNK1γ3 kinase dead mutant suppressed but did not eliminate WNT-driven LRP6 phosphorylation and β-catenin stabilization. Our data suggest that while CSNK1γ3 expression uniquely drives pathway activity, potential functional redundancy within the family necessitates loss of all three family members to suppress the WNT signaling pathway.
2022-06-09 | PXD032138 | Pride