Regulation of Epithelial-Mesenchymal Transition by Transmission of Mechanical Stress through Epithelial Tissues

Gjorevski, Nikolce; Boghaert, Eline; Nelson, Celeste M.

doi:10.1007/s12307-011-0076-5

Cited by 84 publications

(88 citation statements)

References 102 publications

(149 reference statements)

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“…FAK plays an important role in cell adhesion, spreading, motility, invasion and angiogenesis (Schlaepfer et al, 2004). Recently, FAK was reported to play an important role in epithelial to mesenchymal transition (EMT) (Fan et al, 2013;Gjorevski et al, 2012;Golubovskaya, 2014). As a cytoplasmic tyrosine kinase, FAK has been identified as a key mediator of intracellular signaling by integrins, a major family of cell surface receptors for extracellular matrix, in the regulation of different cellular functions in a variety of cells (Aplin et al, 1998;Mehta, 2012).…”

Section: Discussionmentioning

confidence: 99%

Expression of microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4

Li²,

et al. 2014

Journal of Cell Science

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The microRNA miR-17-92 cluster plays a fundamental role in heart development. The aim of this study was to investigate the effect of a member of this cluster, miR-17, on cardiac senescence. We examined the roles of miR-17 in senescence and demonstrated that miR-17-3p attenuates cardiac aging in the myocardium by targeting Par4 (also known as PAWR). This upregulates the downstream proteins CEBPB, FAK, N-cadherin, vimentin, Oct4 and Sca-1 (also known as stem cell antigen-1), and downregulates E-cadherin. Par4 has been reported as a tumor suppressor gene that induces apoptosis in cancer cells, but not in normal cells. Repression of Par4 by miR-17-3p enhances the transcription of CEBPB and FAK, which promotes mouse cardiac fibroblast (MCF) epithelial-tomesenchymal transition (EMT) and self-renewal, resulting in cellular senescence and apoptosis resistance. We conclude that Par4 can bind to the CEBPB promoter and inhibit its transcription. Decreased Par4 expression increases the amount of CEBPB, which binds to the FAK promoter and enhances FAK transcription. Par4, CEBPB and FAK form a senescence signaling pathway, playing roles in modulating cell survival, growth, apoptosis, EMT and self-renewal. Through this novel senescence signaling axis, miR-17-3p represses Par4 expression, acting pleiotropically as a negative modulator of cardiac aging and cardiac fibroblast cellular senescence.

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Section: Discussionmentioning

confidence: 99%

Expression of microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4

Li²,

et al. 2014

Journal of Cell Science

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“…There are apical or basal actin networks, and also connected actin cables that span multiple pairs of cells (Baum and Georgiou 2011). Some actin bundles are linked to apical junctions via adaptor proteins such as catenins, NF2, and AMOT, and these physical connections will create continuity between actin cytoskeletons of neighboring cells (Gjorevski et al 2012); in addition, these adaptor proteins may regulate activity of cdc42 and PAK1-Rac, thereby modulating the apical actin dynamics (Kissil et al 2003;Perez-Moreno and Fuchs 2006;Wells et al 2006). Therefore, it is possible that the phenotypes of NF2, AMOT, a-catenin, and b-catenin deficiency on Yki/YAP/TAZ activity and cell proliferation are mediated by local actin rearrangements.…”

Section: Extracellular Matrix (Ecm) and Cytoskeleton: Sensing Mechanimentioning

confidence: 99%

The Hippo pathway: regulators and regulations

2013

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Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Here, we review regulatory mechanisms of the Hippo pathway and discuss potential implications involved in different physiological and pathological conditions.

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“…In addition, ECM stiffness is also a potent inducer of EMT-like effects (see Sect. 4 below) (Gjorevski et al 2012 ) . It is important to note that most of these cues have been implicated in directing differentiation or proliferation in embryonic development, or as "niche" factors for adult stem cells (Dreesen and Brivanlou 2007 ) .…”

Section: Role Of Scribble As Adaptor For Yap/taz Regulation By the Himentioning

confidence: 99%

“…Conversely, it is also possible that tumor cells with disturbed apico-basal polarity-by partial EMT or mutation/ inactivation of polarity factors, or exposed to high levels of TGF b -may also display increased sensitivity to mechanical gradients. Perhaps this may explain the exquisite spatial and temporal speci fi city of EMT induction so far observed in vivo, being transiently induced in one cell, and not in the adjacent cell, for example during wound healing and tumor progression (Gjorevski et al 2012 ;Thiery et al 2009 ) .…”

Section: Combining Soluble and Unsoluble Cuesmentioning

confidence: 99%

“…Clearly, TGF b is a very effective inducer of EMT in cells cultured on plastic, that is, a very stiff substrate (Heldin et al 2009 ;Zavadil and Bottinger 2005 ) . Intriguingly, however, when monolayers of cells grown on 2D or 3D molds of de fi ned shapes were challenged with TGF b , a clear spatial pattern emerged: only cells experiencing high mechanical stresses, that is, those located at edges, sharp curvatures or tips underwent EMT (Gjorevski et al 2012 ;Gomez et al 2010 ;Lee et al 2011 ) . Conversely, it is also possible that tumor cells with disturbed apico-basal polarity-by partial EMT or mutation/ inactivation of polarity factors, or exposed to high levels of TGF b -may also display increased sensitivity to mechanical gradients.…”

Section: Combining Soluble and Unsoluble Cuesmentioning

confidence: 99%

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Regulation of YAP and TAZ by Epithelial Plasticity

Piccolo

Cordenonsi

2013

The Hippo Signaling Pathway and Cancer

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The Hippo transducers YAP and TAZ are central mediators of organ growth and tumorigenesis, regulating cell proliferation, differentiation, and epithelial stemness. In this chapter, we summarize recent fi ndings linking the activation of YAP and TAZ to the cell's structural and architectural features, such as cell polarity, cell shape, cell adhesion, and cytoskeletal dynamics. We examine how epithelial "plasticity" induced by epithelial-to-mesenchymal transition (EMT) promotes "Cancer Stem Cell" identity and YAP/TAZ activation, and discuss the role of TAZ as molecular determinant of self-renewal and tumor-seeding potentials in cancer cells. YAP and TAZ activation can also induce EMT, generating a self-sustaining loop. We then place special emphasis on biomechanical cues as regulators of epithelial plasticity, and as dominant regulators of YAP and TAZ nuclear localization and transcriptional activities. This regulation is mediated by physical forces, such as rigidity of the extracellular matrix, and tension of the actomyosin cytoskeleton. These mechanical signals hold in shape individual cells and whole tissues, and are severely disturbed in cancer. In sum, we highlight new mechanisms of YAP and TAZ regulation by cell polarity and mechanical cues. This potentially adds a new dimension to our understanding of physiology and tumorigenesis, whereby the behavior of individual cells is dictated by the integration of information about tissue architecture and mechanics mediated by YAP and TAZ.

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Regulation of Epithelial-Mesenchymal Transition by Transmission of Mechanical Stress through Epithelial Tissues

Cited by 84 publications

References 102 publications

Expression of microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4

Expression of microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4

The Hippo pathway: regulators and regulations

Regulation of YAP and TAZ by Epithelial Plasticity

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