scholarly journals Snail1: A Transcriptional Factor Controlled at Multiple Levels

2019 ◽  
Vol 8 (6) ◽  
pp. 757 ◽  
Author(s):  
Josep Baulida ◽  
Víctor M. Díaz ◽  
Antonio García de Herreros
Keyword(s):  
Gene Transcription ◽  
Epithelial To Mesenchymal Transition ◽  
Transcriptional Repressor ◽  
Transcriptional Factor ◽  
Protein Modifications ◽  
Mesenchymal Transition ◽  
Fibroblast Activation ◽  
Multiple Levels ◽  
And Function ◽  
Snail1 Expression

Snail1 transcriptional factor plays a key role in the control of epithelial to mesenchymal transition and fibroblast activation. As a consequence, Snail1 expression and function is regulated at multiple levels from gene transcription to protein modifications, affecting its interaction with specific cofactors. In this review, we describe the different elements that control Snail1 expression and its activity both as transcriptional repressor or activator.

scholarly journals PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

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 α-catenin facilitates mechanosensing and rigidity-dependent growth by linking integrin adhesions to F-actin

2021 ◽  
Author(s):  
Abhishek Mukherjee ◽  
Elisabeth Nadjar-Boger ◽  
Michael P. Sheetz ◽  
Haguy Wolfenson
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Force Transmission ◽  
Mesenchymal Transition ◽  
Cell Edge ◽  
Cell Matrix ◽  
The Matrix ◽  
Cell Adhesions ◽  
Dependent Growth ◽  
And Function ◽  
Cell Cell

AbstractThe physical interactions of cells with their external environment are critical for their survival and function. These interactions are altered upon epithelial to mesenchymal transition (EMT) as cells switch from relying primarily on cell-cell adhesions to relying on cell-matrix adhesions. Mechanical signals are central to regulating these two types of interactions, but the crosstalk and the mechanobiological processes that mediate the transition between them are poorly understood. Here we show that α-catenin, a mechanosensitive protein that regulates cadherin-based cell-cell adhesions, directly interacts with integrin adhesions and regulates their growth as well as their transmission of mechanical forces into the matrix. In mesenchymal cells, α-catenin is recruited to the cell edge where it interacts with actin in regions devoid of α-actinin. As actin and α-catenin flow from the cell edge toward the center, α-catenin interacts with vinculin within integrin adhesions to mediate adhesion maturation, enhance force transmission, and drive the proper assembly of actin stress fibers. Importantly, in the absence of α-catenin–vinculin interactions, cell adhesion to the matrix is impaired, and the cells display aberrant responses to matrix rigidity which is manifested in rigidity-independent growth. These results provide a novel understanding of α-catenin as having a dual-role in mechanosensing by both cell-cell and cell-matrix adhesions.

scholarly journals Implications of ABCC4–Mediated cAMP Efflux for CRC Migration

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3547
Author(s):  
Jakub Kryczka ◽  
Ewelina Sochacka ◽  
Izabela Papiewska-Pająk ◽  
Joanna Boncela
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Gene Expression Omnibus ◽  
Functional Study ◽  
Molecular Heterogeneity ◽  
Dependent Manner ◽  
Key Factors ◽  
Mesenchymal Transition ◽  
Abc Protein ◽  
Important Regulator ◽  
And Function

Colorectal cancer (CRC) presents significant molecular heterogeneity. The cellular plasticity of epithelial to mesenchymal transition (EMT) is one of the key factors responsible for the heterogeneous nature of metastatic CRC. EMT is an important regulator of ATP binding cassette (ABC) protein expression; these proteins are the active transporters of a broad range of endogenous compounds and anticancer drugs. In our previous studies, we performed a transcriptomic and functional analysis of CRC in the early stages of metastasis induced by the overexpression of Snail, the transcription factor involved in EMT initiation. Interestingly, we found a correlation between the Snail expression and ABCC4 (MRP4) protein upregulation. The relationship between epithelial transition and ABCC4 expression and function in CRC has not been previously defined. In the current study, we propose that the ABCC4 expression changes during EMT and may be differentially regulated in various subpopulations of CRC. We confirmed that ABCC4 upregulation is correlated with the phenotype conversion process in CRC. The analysis of Gene Expression Omnibus (GEO) sets showed that the ABCC4 expression was elevated in CRC patients. The results of a functional study demonstrated that, in CRC, ABCC4 can regulate cell migration in a cyclic nucleotide-dependent manner.

scholarly journals Protein complexes that control renal epithelial polarity

2011 ◽  
Vol 300 (3) ◽  
pp. F589-F601 ◽  
Author(s):  
Jay Pieczynski ◽  
Ben Margolis
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Kidney Development ◽  
Protein Complexes ◽  
Basolateral Membrane ◽  
Protein Activity ◽  
Mesenchymal Transition ◽  
Apicobasal Polarity ◽  
Mesenchymal To Epithelial Transition ◽  
And Function ◽  
Crumbs Complex

Establishment of epithelial apicobasal polarity is crucial for proper kidney development and function. In recent years, there have been important advances in our understanding of the factors that mediate the initiation of apicobasal polarization. Key among these are the polarity complexes that are evolutionarily conserved from simple organisms to humans. Three of these complexes are discussed in this review: the Crumbs complex, the Par complex, and the Scribble complex. The apical Crumbs complex consists of three proteins, Crumbs, PALS1, and PATJ, whereas the apical Par complex consists of Par-3, Par-6, and atypical protein kinase C. The lateral Scribble complex consists of Scribble, discs large, and lethal giant larvae. These complexes modulate kinase and small G protein activity such that the apical and basolateral complexes signal antagonistically, leading to the segregation of the apical and basolateral membranes. The polarity complexes also serve as scaffolds to direct and retain proteins at the apical membrane, the basolateral membrane, or the intervening tight junction. There is plasticity in apicobasal polarity, and this is best seen in the processes of epithelial-to-mesenchymal transition and the converse mesenchymal-to-epithelial transition. These transitions are important in kidney disease as well as kidney development, and modulation of the polarity complexes are critical for these transitions.

scholarly journals Emerging Role for Epithelial Polarity Proteins of the Crumbs Family as Potential Tumor Suppressors

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Patrick Laprise
Keyword(s):  
Tumor Suppressors ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Tissue Growth ◽  
Epithelial Polarity ◽  
Mesenchymal Transition ◽  
Full Complement ◽  
Polarity Proteins ◽  
And Function ◽  
And Control

Defects in apical-basal polarity regulation are associated with tissue overgrowth and tumorogenesis, yet the molecular mechanisms linking epithelial polarity regulators to hyperplasia or neoplasia remain elusive. In addition, exploration of the expression and function of the full complement of proteins required for the polarized architecture of epithelial cells in the context of cancer is awaited. This paper provides an overview of recent studies performed onDrosophilaand vertebrates showing that apical polarity proteins of the Crumbs family act to repress tissue growth and epithelial to mesenchymal transition. Thus, these proteins emerge as potential tumor suppressors. Interestingly, analysis of the molecular function of Crumbs proteins reveals a function for these polarity regulators in junctional complexes stability and control of signaling pathways regulating proliferation and apoptosis. Thereby, these studies provide a molecular basis explaining how regulation of epithelial polarity is coupled to tumorogenesis.

scholarly journals Expression of Fibroblast Activation Protein Is Enriched in Neuroendocrine Prostate Cancer and Predicts Worse Survival

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 135
Author(s):  
Panagiotis J. Vlachostergios ◽  
Athanasios Karathanasis ◽  
Vassilios Tzortzis
Keyword(s):  
Prostate Cancer ◽  
Mrna Expression ◽  
Epithelial To Mesenchymal Transition ◽  
Fibroblast Activation Protein ◽  
Castration Resistant Prostate Cancer ◽  
Sequencing Data ◽  
Clinical Value ◽  
Mesenchymal Transition ◽  
Fibroblast Activation ◽  
Neuroendocrine Prostate Cancer

Background: Advanced prostate cancer (PC) may accumulate genomic alterations that hallmark lineage plasticity and transdifferentiation to a neuroendocrine (NE) phenotype. Fibroblast activation protein (FAP) is a key player in epithelial-to-mesenchymal transition (EMT). However, its clinical value and role in NE differentiation in advanced PC has not been fully investigated. Methods: Two hundred and eight patients from a multicenter, prospective cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with available RNA sequencing data were analyzed for tumor FAP mRNA expression, and its association with overall survival (OS) and NE tumor features was investigated. Results: Twenty-one patients (10%) were found to have high FAP mRNA expression. Compared to the rest, this subset had a proportionally higher exposure to taxanes and AR signaling inhibitors (abiraterone or enzalutamide) and was characterized by active NE signaling, evidenced by high NEPC- and low AR-gene expression scores. These patients with high tumor mRNA FAP expression had a more aggressive clinical course and significantly shorter survival (12 months) compared to those without altered FAP expression (28 months, log-rank p = 0.016). Conclusions: FAP expression may serve as a valuable NE marker indicating a worse prognosis in patients with metastatic CRPC.

scholarly journals Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region

2021 ◽  
Author(s):  
Karim Abu Nahia ◽  
Maciej Migdał ◽  
T. Alexander Quinn ◽  
Kar-Lai Poon ◽  
Maciej Łapiński ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Fluorescent Protein ◽  
Building Blocks ◽  
Transgenic Zebrafish ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Protein Coding ◽  
Mesenchymal Transition ◽  
Molecular Building Blocks ◽  
And Function

AbstractThe atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-β, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.

scholarly journals HMGA2 and Smads Co-regulate SNAIL1 Expression during Induction of Epithelial-to-Mesenchymal Transition

2008 ◽  
Vol 283 (48) ◽  
pp. 33437-33446 ◽  
Author(s):  
Sylvie Thuault ◽  
E-Jean Tan ◽  
Hector Peinado ◽  
Amparo Cano ◽  
Carl-Henrik Heldin ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Snail1 Expression
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