scholarly journals Neurogenin regulates effectors of migratory neuron cell behaviors in Ciona

2019 ◽  
Author(s):  
Susanne Gibboney ◽  
Kwantae Kim ◽  
Florian Razy-Krajka ◽  
Wei Wang ◽  
Alberto Stolfi
Keyword(s):  
Candidate Genes ◽  
Epithelial To Mesenchymal Transition ◽  
Model System ◽  
Dominant Negative ◽  
Mesenchymal Transition ◽  
Cell Behaviors ◽  
Developmental Program ◽  
Gene Functions ◽  
Transcriptional Output ◽  
Tgfβ Pathway

AbstractThe bipolar tail neurons (BTNs) of Ciona develop according to a highly dynamic, yet highly stereotyped developmental program and thus could serve as an accessible model system for neuronal delamination, migration, and polarized axon outgrowth. Here we used FACS/RNAseq to profile the transcriptional output of Neurogenin in the BTNs, searching for candidate effectors of BTN cell behaviors. We identified several candidate genes that might play conserved roles in similar cell behaviors in other animals, including mammals. Among the more interesting candidates were several microtubule-binding proteins and TGFβ pathway antagonists. A small Gαi subunit was also found to be upregulated in migrating BTNs, and interfering with its function through expression of a dominant negative inhibited delamination and a complete epithelial-to-mesenchymal transition. We propose models for the regulation of BTN behaviors by the identified candidate effectors, establishing a foundation for testing effector gene functions that might be conserved in chordate neurodevelopment.

scholarly journals USP11 augments TGFβ signalling by deubiquitylating ALK5

Open Biology ◽  
2012 ◽  
Vol 2 (6) ◽  
pp. 120063 ◽  
Author(s):  
Mazin A. Al-Salihi ◽  
Lina Herhaus ◽  
Thomas Macartney ◽  
Gopal P. Sapkota
Keyword(s):  
Gene Transcription ◽  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Type I ◽  
Negative Effects ◽  
Transcriptional Responses ◽  
Mesenchymal Transition ◽  
Tgfβ Receptors ◽  
Tgfβ Signalling ◽  
Tgfβ Pathway

Summary The TGFβ receptors signal through phosphorylation and nuclear translocation of SMAD2/3. SMAD7, a transcriptional target of TGFβ signals, negatively regulates the TGFβ pathway by recruiting E3 ubiquitin ligases and targeting TGFβ receptors for ubiquitin-mediated degradation. In this report, we identify a deubiquitylating enzyme USP11 as an interactor of SMAD7. USP11 enhances TGFβ signalling and can override the negative effects of SMAD7. USP11 interacts with and deubiquitylates the type I TGFβ receptor (ALK5), resulting in enhanced TGFβ-induced gene transcription. The deubiquitylase activity of USP11 is required to enhance TGFβ-induced gene transcription. RNAi -mediated depletion of USP11 results in inhibition of TGFβ-induced SMAD2/3 phosphorylation and TGFβ-mediated transcriptional responses. Central to TGFβ pathway signalling in early embryogenesis and carcinogenesis is TGFβ-induced epithelial to mesenchymal transition. USP11 depletion results in inhibition of TGFβ-induced epithelial to mesenchymal transition.

scholarly journals Fra1 is required for TGFβ1 induced collective invasion

2020 ◽  
Author(s):  
Sharon Camacho ◽  
Apsra Nasir ◽  
Raneen Rahhal ◽  
Maia Dominguez ◽  
Gray W. Pearson
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Growth Factor Receptor ◽  
Genetically Engineered ◽  
Primary Tumors ◽  
Pathway Activity ◽  
Mesenchymal Transition ◽  
Extracellular Signal ◽  
Collective Invasion ◽  
Epidermal Growth ◽  
Tgfβ Pathway

ABSTRACTCells that lead collective invasion can have distinct traits and regulatory programs compared to the cells that follow them. Notably, a specific type of epithelial-to-mesenchymal transition (EMT) program we term a “trailblazer EMT” endows cells with the ability to lead collective invasion and promote the opportunistic invasion of intrinsically less invasive siblings. Here, we sought to define the regulatory programs that are responsible for inducing a trailblazer EMT in a genetically engineered mouse (GEM) model of breast cancer. Analysis of fresh tumor explants, cultured organoids and cell lines revealed that the trailblazer EMT was controlled by TGFβ pathway activity that induced a hybrid EMT state characterized by cells expressing E-cadherin and Vimentin. Notably, the trailblazer EMT was active in cells lacking keratin 14 expression and evidence of trailblazer EMT activation was detected in collectively invading cells in primary tumors. The trailblazer EMT program required expression of the transcription factor Fra1, which was regulated by the parallel autocrine activation of the epidermal growth factor receptor (EGFR) and extracellular signal regulated kinases (ERK) 1 and 2. Together, these results reveal that the activity of parallel TGFβ and EGFR pathways confers cells with the ability to lead collective invasion through the induction of a trailblazer EMT.

scholarly journals “Neur”al brain wave: Coordinating epithelial-to-neural stem cell transition in the fly optic lobe

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Arnaud Ambrosini ◽  
Katja Röper
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Optic Lobe ◽  
Tissue Level ◽  
Cell Alignment ◽  
Brain Wave ◽  
Apical Constriction ◽  
Mesenchymal Transition ◽  
Cell Behaviors ◽  
Crumbs Complex ◽  
Cell Transition

In the Drosophila larval optic lobe, the generation of neural stem cells involves an epithelial-to-mesenchymal–like transition of a continuous stripe of cells that sweeps across the neuroepithelium, but the dynamics at cell and tissue level were unknown until now. In this issue, Shard et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202005035) identify that Neuralized controls a partial epithelial-to-mesenchymal transition through regulation of the apical Crumbs complex and through the coordination of cell behaviors such as apical constriction and cell alignment.

scholarly journals SMAD4 and the TGFβ Pathway in Patients with Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 21 (10) ◽  
pp. 3534
Author(s):  
Julie Dardare ◽  
Andréa Witz ◽  
Jean-Louis Merlin ◽  
Pauline Gilson ◽  
Alexandre Harlé
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Tgfβ Signaling ◽  
Potent Inducer ◽  
Mesenchymal Transition ◽  
Tgfβ Pathway

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide. PDAC is an aggressive disease with an 11-month median overall survival and a five-year survival of less than 5%. Incidence of PDAC is constantly increasing and is predicted to become the second leading cause of cancer in Western countries within a decade. Despite research and therapeutic development, current knowledge about PDAC molecular mechanisms still needs improvements and it seems crucial to identify novel therapeutic targets. Genomic analyses of PDAC revealed that transforming growth factor β (TGFβ) signaling pathways are modified and the SMAD4 gene is altered in 47% and 60% of cases, respectively, highlighting their major roles in PDAC development. TGFβ can play a dual role in malignancy depending on the context, sometimes as an inhibitor and sometimes as an inducer of tumor progression. TGFβ signaling was identified as a potent inducer of epithelial-to-mesenchymal transition (EMT), a process that confers migratory and invasive properties to epithelial cells during cancer. Therefore, aberrant TGFβ signaling and EMT are linked to promoting PDAC aggressiveness. TGFβ and SMAD pathways were extensively studied but the mechanisms leading to cancer promotion and development still remain unclear. This review aims to describe the complex role of SMAD4 in the TGFβ pathway in patients with PDAC.

scholarly journals EIF5A2 controls ovarian tumor growth and metastasis by promoting epithelial to mesenchymal transition via the TGFβ pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Guannan Zhao ◽  
Wenjing Zhang ◽  
Peixin Dong ◽  
Hidemichi Watari ◽  
Yuqi Guo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Ovarian Tumor ◽  
Tumor Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
Tumor Growth And Metastasis ◽  
Tgfβ Pathway

Abstract Background Epithelial to mesenchymal transition (EMT) contributes to tumor metastasis and chemoresistance. Eukaryotic initiation factor 5A2 (EIF5A2) is highly expressed in a variety of human cancers but rarely expressed in normal tissues. While EIF5A2 has oncogenic activity in several cancers and contributes to tumor metastasis, its role in ovarian cancer is unknown. In this study, we investigate whether EIF5A2 contributes to ovarian tumor metastasis by promoting EMT. Methods To investigate the role of EIF5A2, we knocked out (KO) EIF5A2 using lentiviral CRISPR/Cas9 nickase in high invasive SKOV3 and OVCAR8 cells and overexpressed EIF5A2 in low invasive OVCAR3 cells using lentiviral vector. Cell proliferation, migration and invasion was examined in vitro ovarian cancer cells and tumor metastasis was evaluated in vivo using orthotopic ovarian cancer mouse models. Results Here we report that EIF5A2 is highly expressed in ovarian cancers and associated with patient poor survival. Lentiviral CRISPR/Cas9 nickase vector mediated knockout (KO) of EIF5A2 inhibits epithelial to mesenchymal transition (EMT) in SKOV3 and OVCAR8 ovarian cancer cells that express high levels of EIF5A2. In contrast, overexpression of EIF5A2 promotes EMT in OVCAR3 epithelial adenocarcinoma cells that express relatively low EIF5A2 levels. KO of EIF5A2 in SKOV3 and OVCAR8 cells inhibits ovarian cancer cell migration and invasion, while its overexpression promotes cell migration and invasion in OVCAR3 adenocarcinoma cells. We further demonstrate that EIF5A2 promotes EMT by activating the TGFβ pathway and KO of EIF5A2 inhibits ovarian tumor growth and metastasis in orthotopic ovarian cancer mouse models. Conclusion Our results indicate that EIF5A2 is an important controller of ovarian tumor growth and metastasis by promoting EMT and activating the TGFβ pathway.

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