| 1. |
- Buechel, David, et al.
(författare)
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Parsing beta-catenins cell adhesion and Wnt signaling functions in malignant mammary tumor progression
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 118:34
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Tidskriftsartikel (refereegranskat)abstract
- During malignant progression, epithelial cancer cells dissolve their cell-cell adhesion and gain invasive features. By virtue of its dual function, beta-catenin contributes to cadherin-mediated cell-cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bd9 and Pygo-pus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of beta-catenins transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)-PyMT mouse model of metastatic breast cancer, we compared the complete elimination of beta-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of beta-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of beta-catenins transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial-mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by beta-catenins transcriptional activities upon stimulation with Wnt3a or during TGF-beta-induced EMT. Our results uncouple the signaling from the adhesion function of beta-catenin and underline the importance of Wnt/beta-catenin-dependent transcription in malignant tumor progression of breast cancer.
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| 2. |
- Cantù, Claudio, et al.
(författare)
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A cytoplasmic role of Wnt/β-catenin transcriptional cofactors Bcl9, Bcl9l, and Pygopus in tooth enamel formation.
- 2017
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 10:465
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Tidskriftsartikel (refereegranskat)abstract
- Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate with β-catenin. In the nucleus, Bcl9 and Bcl9l simultaneously bind β-catenin and the transcriptional activator Pygo2 to promote the transcription of a subset of Wnt target genes. We showed that Bcl9 and Bcl9l function in the cytoplasm during tooth enamel formation in a manner that is independent of Wnt-stimulated β-catenin-dependent transcription. Bcl9, Bcl9l, and Pygo2 localized mainly to the cytoplasm of the epithelial-derived ameloblasts, the cells responsible for enamel production. In ameloblasts, Bcl9 interacted with proteins involved in enamel formation and proteins involved in exocytosis and vesicular trafficking. Conditional deletion of both Bcl9 and Bcl9l or both Pygo1 and Pygo2 in mice produced teeth with defective enamel that was bright white and deficient in iron, which is reminiscent of human tooth enamel pathologies. Overall, our data revealed that these proteins, originally defined through their function as β-catenin transcriptional cofactors, function in odontogenesis through a previously uncharacterized cytoplasmic mechanism, revealing that they have roles beyond that of transcriptional cofactors.
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| 3. |
- Cantù, Claudio, et al.
(författare)
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A RING finger to wed TCF and β-catenin
- 2013
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Ingår i: EMBO Reports. - : Wiley-Blackwell Publishing Inc.. - 1469-221X .- 1469-3178. ; 14:4, s. 295-296
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Cantù, Claudio, et al.
(författare)
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Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/beta-catenin signaling
- 2018
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Ingår i: Genes & Development. - : COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. - 0890-9369 .- 1549-5477. ; 32:21-22, s. 1443-1458
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Tidskriftsartikel (refereegranskat)abstract
- Bcl9 and Pygopus (Pygo) are obligate Wnt/beta-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, beta-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the beta-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective beta-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.
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| 5. |
- Cantù, Claudio, et al.
(författare)
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Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development.
- 2014
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Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 28:17, s. 1879-84
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Tidskriftsartikel (refereegranskat)abstract
- Bcl9 and Bcl9l (Bcl9/9l) encode Wnt signaling components that mediate the interaction between β-catenin and Pygopus (Pygo) via two evolutionarily conserved domains, HD1 and HD2, respectively. We generated mouse strains lacking these domains to probe the β-catenin-dependent and β-catenin-independent roles of Bcl9/9l and Pygo during mouse development. While lens development is critically dependent on the presence of the HD1 domain, it is not affected by the lack of the HD2 domain, indicating that Bcl9/9l act in this context in a β-catenin-independent manner. Furthermore, we uncover a new regulatory circuit in which Pax6, the master regulator of eye development, directly activates Bcl9/9l transcription.
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| 6. |
- Cantù, Claudio, et al.
(författare)
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Unexpected survival of mice carrying a mutation in Pygo2 that strongly reduces its binding to Bcl9/9l
- 2016
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Ingår i: Matters Select. - Zürich : ScienceMatters AG. - 2297-9239.
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Tidskriftsartikel (refereegranskat)abstract
- Pygopus is a transcriptional activator important for the Wnt signaling pathway. It binds to the beta-catenin transcriptional complex via the adaptor proteins Bcl9 and Bcl9l (Bcl9/9l). This complex is considered to be a suitable target for the treatment of tumors that display activated Wnt signaling. In the mouse, there are two Pygopus-encoding genes, Pygo1 and Pygo2 (Pygo1/2), with the latter playing a major role. Here we introduce a single amino acid substitution in Pygo2, which was previously shown to abrogate binding to Bcl9/9l, and cause lethality in Drosophila melanogaster. We confirm that mutant Pygo2 protein fails in interacting with Bcl9 but, unexpectedly, homozygous mice with this mutation are viable and fertile, even when this mutant allele is combined with a null mutation of the potentially redundant Pygo1. Based on this observation, we conjecture that the Pygo-Bcl9/9l interaction requires scant affinity in vivo to fulfill developmental functions and thrust forward the notion that this interaction surface could be targeted in cancer therapy without major consequences on homeostatic functions.
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| 7. |
- Diener, Johanna, et al.
(författare)
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Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4
- 2021
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Ingår i: Nature Communications. - : Nature Portfolio. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::Nras(Q61K); Cdkn2a(-/-) melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism. Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.
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| 8. |
- Doumpas, Nikolaos, et al.
(författare)
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TCF/LEF dependent and independent transcriptional regulation of Wnt/beta-catenin target genes
- 2019
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Ingår i: EMBO Journal. - : WILEY. - 0261-4189 .- 1460-2075. ; 38:2
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Tidskriftsartikel (refereegranskat)abstract
- During canonical Wnt signalling, the activity of nuclear beta-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of beta-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that beta-catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed the existence of a transcriptional activity of beta-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as beta-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of beta-catenin that bypasses the TCF/LEF transcription factors.
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| 9. |
- Doumpas, Nikolaos, et al.
(författare)
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TCF/LEF regulation of the topologically associated domain ADI promotes mESCs to exit the pluripotent ground state
- 2021
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 36:11
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Tidskriftsartikel (refereegranskat)abstract
- Mouse embryonic stem cells (mESCs) can bemaintained in vitro in defined N2B27 medium supplemented with two chemical inhibitors for GSK3 and MEK (2i) and the cytokine leukemia inhibitory factor (LIF), which act synergistically to promote self-renewal and pluripotency. Here, we find that genetic deletion of the four genes encoding the TCF/LEF transcription factors confersm ESCs with the ability to self-renew in N2B27 medium alone. TCF/LEF quadruple knockout (qKO) mESCs display dysregulation of several genes, including Aire, Dnmt3l, and IcosL, located adjacent to each other within a topologically associated domain (TAD). Aire, Dnmt3l, and IcosL appear to be regulated by TCF/LEF in a beta-catenin independent manner. Moreover, downregulation of Aire and Dnmt3l in wild-type mESCs mimics the loss of TCF/LEF and increases mESC survival in the absence of 2iL. Hence, this study identifies TCF/LEF effectors that mediate exit from the pluripotent state.
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| 10. |
- Draganova, Kalina, et al.
(författare)
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Wnt/β‐Catenin Signaling Regulates Sequential Fate Decisions of Murine Cortical Precursor Cells
- 2015
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Ingår i: Stem Cells. - Durham, United States : AlphaMed Press, Inc.. - 1066-5099 .- 1549-4918. ; 33:1, s. 170-182
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Tidskriftsartikel (refereegranskat)abstract
- The fate of neural progenitor cells (NPCs) is determined by a complex interplay of intrinsic programs and extrinsic signals, very few of which are known. β-Catenin transduces extracellular Wnt signals, but also maintains adherens junctions integrity. Here, we identify for the first time the contribution of β-catenin transcriptional activity as opposed to its adhesion role in the development of the cerebral cortex by combining a novel β-catenin mutant allele with conditional inactivation approaches. Wnt/β-catenin signaling ablation leads to premature NPC differentiation, but, in addition, to a change in progenitor cell cycle kinetics and an increase in basally dividing progenitors. Interestingly, Wnt/β-catenin signaling affects the sequential fate switch of progenitors, leading to a shortened neurogenic period with decreased number of both deep and upper-layer neurons and later, to precocious astrogenesis. Indeed, a genome-wide analysis highlighted the premature activation of a corticogenesis differentiation program in the Wnt/β-catenin signaling-ablated cortex. Thus, β-catenin signaling controls the expression of a set of genes that appear to act downstream of canonical Wnt signaling to regulate the stage-specific production of appropriate progenitor numbers, neuronal subpopulations, and astroglia in the forebrain.
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