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Journal ArticleDOI

An emergent Wnt5a/YAP/TAZ regulatory circuit and its possible role in cancer

TL;DR: In this paper, the authors proposed that Wnt5a is integrated within a larger regulatory circuit involving β-catenin, YAP/TAZ, and LATS1/2.
About: This article is published in Seminars in Cell & Developmental Biology.The article was published on 2021-11-08 and is currently open access. It has received 7 citations till now. The article focuses on the topics: WNT5A & Biology.
Citations
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Journal ArticleDOI
TL;DR: An updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings is provided.
Abstract: Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.

3 citations

Journal ArticleDOI
TL;DR: Pulmonary arterial hypertension (PAH) is a chronic, progressive and rapidly fatal disease with a poor prognosis, high mortality rate and lack of curative treatment options as mentioned in this paper .
Abstract: Pulmonary arterial hypertension (PAH) is a chronic, progressive and rapidly fatal disease with a poor prognosis, high mortality rate and lack of curative treatment options [1], defined by a mean pulmonary artery (PA) pressure greater than 20 mmHg at a rest [2, 3]. The main pathophysiological features of PAH include vasoconstriction, remodelling of small muscular PAs and perivascular inflammation [4]. PAH is a multifactorial disease. Genetic pre-disposition, epigenetic events, environmental exposure and other underlying conditions trigger endothelial cell (EC) apoptosis, leading to vascular pruning and loss of microvasculature, as well as cancer-like hyper-proliferation and survival of PA smooth muscle cells (PASMCs), PAECs and PA adventitial fibroblasts, and obstruction of small muscular PAs [1, 4, 5]. The functional and structural microvascular rarefaction results in the reduction in cross-sectional lumen area and in unresolved increase in right ventricular (RV) afterload, leading to premature death from right heart failure [6]. Dysbalanced Wnt signalling promotes pulmonary arterial hypertension http://bit.ly/3ZvuNXf
Journal ArticleDOI
TL;DR: Li et al. as mentioned in this paper analyzed the transcriptomes of csal1 and empty vector in Chinese Dagu hens by RNA sequencing and found that the DEGs in GCs of ovarian follicles were enriched in neuroactive ligand-receptor interaction, cell adhesion molecules, and pathways related to cytochrome P450.
Posted ContentDOI
05 May 2023-bioRxiv
TL;DR: In this article , a noisy Boolean logic Bayesian model for TF activity inference from differential gene expression data and causal graphs is presented, which can accurately identify TF activity using simulations and controlled over-expression experiments in cell cultures.
Abstract: The advent of high-throughput sequencing has made it possible to measure the expression of genes at relatively low cost. However, direct measurement of regulatory mechanisms, such as Transcription Factor (TF) activity is still not readily feasible in a high-throughput manner. Consequently, there is a need for computational approaches that can reliably estimate regulator activity from observable gene expression data. In this work, we present a noisy Boolean logic Bayesian model for TF activity inference from differential gene expression data and causal graphs. Our approach provides a flexible framework to incorporate biologically motivated TF-gene regulation logic models. Using simulations and controlled over-expression experiments in cell cultures, we demonstrate that our method can accurately identify TF activity. Moreover, we apply our method to bulk and single cell transcriptomics measurements to investigate transcriptional regulation of fibroblast phenotypic plasticity. Finally, to facilitate usage, we provide user-friendly software packages and a web-interface to query TF activity from user input differential gene expression data: https://umbibio.math.umb.edu/nlbayes/. Author Summary NextGen RNA sequencing (RNA-Seq) has enabled simultaneous measurement of the expression level of all genes. Measurements can be done at the population level or single-cell resolution. However, direct measurement of regulatory mechanisms, such as Transcription Factor (TF) activity, is still not possible in a high-throughput manner. As such, there is a need for computational models to infer regulator activity from gene expression data. In this work, we introduce a Bayesian methodology that utilizes prior biological knowledge on bio-molecular interactions in conjunction with readily available gene expression measurements to estimate TF activity. The Bayesian model naturally incorporates biologically motivated combinatorial TF-gene interaction logic models and accounts for noise in gene expression data as well as prior knowledge. The method is accompanied by efficiently implemented R and Python software packages as well as a user-friendly web-based interface that allows users to upload their gene expression data and run queries on a TF-gene interaction network to identify and rank putative transcriptional regulators. This tool can be used for a wide range of applications, such as identification of TFs downstream of signaling events and environmental or molecular perturbations, the aberration in TF activity in diseases, and other studies with ‘case-control’ gene expression data.
References
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Journal ArticleDOI
TL;DR: The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels, and that receptor-ligand specificity and feedback loops help to determine WNT signaling outputs.
Abstract: Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.

5,129 citations

Journal ArticleDOI
TL;DR: Tumors of epithelioma are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.
Abstract: SOLID tumors are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.1 , 2 In tumors of epitheli...

4,132 citations

Journal ArticleDOI
09 Jun 2011-Nature
TL;DR: YAP/TAZ are identified as sensors and mediators of mechanical cues instructed by the cellular microenvironment and are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry.
Abstract: Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.

4,120 citations

Journal ArticleDOI
TL;DR: It is found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation.

3,553 citations

Journal ArticleDOI
25 Nov 2009-Cell
TL;DR: Reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence, and data show how collagenCrosslinking can modulate tissue fibrosis and stiffness to force focal adhesion, growth factor signaling and breast malignancies.

3,396 citations