Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins

Chaqour, Brahim; Goppelt‐Struebe, Margarete

doi:10.1111/j.1742-4658.2006.05360.x

Cited by 165 publications

(131 citation statements)

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“…Although several signaling pathways are activated by cyclic strain in fibroblasts ), reorganization and increase in actin-stress fibers as a result of RhoA activation is a prominent response (SarasaRenedo et al, 2006). Recent evidence indicates that mechanical stress might regulate a specific group of genes directly via a change in RhoA-dependent actin dynamics, among them are genes encoding -smooth muscle actin, CTGF/CCN1, Cyr61/CCN2 and tenascin-C (Chaqour and Goppelt-Struebe, 2006;Chaqour et al, 2007;Schild and Trueb, 2004;Zhao et al, 2007). We have shown previously that induction of tenascin-C by cyclic strain requires the presence of 1 integrin (Chiquet et al, 2006) and ILK (Maier et al, 2008), the activation of RhoA , actin reorganization , and that it correlates with translocation of MAL to the nucleus (Maier et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Pericellular fibronectin is required for RhoA-dependent responses to cyclic strain in fibroblasts

Lutz

Sakai

Chiquet

2010

Journal of Cell Science

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SummaryTo test the hypothesis that the pericellular fibronectin matrix is involved in mechanotransduction, we compared the response of normal and fibronectin-deficient mouse fibroblasts to cyclic substrate strain. Normal fibroblasts seeded on vitronectin in fibronectin-depleted medium deposited their own fibronectin matrix. In cultures exposed to cyclic strain, RhoA was activated, actin-stress fibers became more prominent, MAL/MKL1 shuttled to the nucleus, and mRNA encoding tenascin-C was induced. By contrast, these RhoAdependent responses to cyclic strain were suppressed in fibronectin knockdown or knockout fibroblasts grown under identical conditions. On vitronectin substrate, fibronectin-deficient cells lacked fibrillar adhesions containing5 integrin. However, when fibronectin-deficient fibroblasts were plated on exogenous fibronectin, their defects in adhesions and mechanotransduction were restored. Studies with fragments indicated that both the RGD-synergy site and the adjacent heparin-binding region of fibronectin were required for full activity in mechanotransduction, but not its ability to self-assemble. In contrast to RhoA-mediated responses, activation of Erk1/2 and PKB/Akt by cyclic strain was not affected in fibronectin-deficient cells. Our results indicate that pericellular fibronectin secreted by normal fibroblasts is a necessary component of the strain-sensing machinery. Supporting this hypothesis, induction of cellular tenascin-C by cyclic strain was suppressed by addition of exogenous tenascin-C, which interferes with fibronectinmediated cell spreading.

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Section: Discussionmentioning

confidence: 99%

Pericellular fibronectin is required for RhoA-dependent responses to cyclic strain in fibroblasts

Lutz

Sakai

Chiquet

2010

Journal of Cell Science

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“…It is assumed that the early CA-4P-mediated alterations in endothelial cell morphology ultimately lead to cell death when the cells go through mitosis. Changes in cell morphology, however, may also directly affect gene expression (7). This aspect has not yet been investigated in relation to CA-4P and may affect proteins other than cell cycle regulators.…”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Connective Tissue Growth Factor in Endothelial Cells by the Microtubule-Destabilizing Agent Combretastatin A-4

Samarin

Rehm²,

Krueger³

et al. 2009

Molecular Cancer Research

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Incubation of microvascular endothelial cells with combretastatin A-4 phosphate (CA-4P), a microtubule-destabilizing compound that preferentially targets tumor vessels, altered cell morphology and induced scattering of Golgi stacks. Concomitantly, CA-4P up-regulated connective tissue growth factor (CTGF/CCN2), a pleiotropic factor with antiangiogenic properties. In contrast to the effects of other microtubule-targeting agents such as colchicine or nocodazole, up-regulation of CTGF was only detectable in sparse cells, which were not embedded in a cell monolayer. Furthermore, CA-4P induced CTGF expression in endothelial cells, forming tube-like structures on basement membrane gels. Up-regulation of CTGF by CA-4P was dependent on Rho kinase signaling and was increased when p42/44 mitogen-activated protein kinase was inhibited. Additionally, FoxO transcription factors were identified as potent regulators of CTGF expression in endothelial cells. Activation of FoxO transcription factors by inhibition of phosphatidylinositol 3-kinase/AKT signaling resulted in a synergistic increase in CA-4P-mediated CTGF induction. CA-4P-mediated expression of CTGF was thus potentiated by the inhibition of kinase pathways, which are targets of novel antineoplastic drugs. Up-regulation of CTGF by low concentrations of CA-4P may thus occur in newly formed tumor vessels and contribute to the microvessel destabilization and antiangiogenic effects of CA-4P observed in vivo. (Mol Cancer Res 2009;7(2):180–8)

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“…In vascular smooth muscle cells, remodeling of the arteries in response to mechanical loads -such as changes in blood pressureis also regulated at transcriptional level by the mechanosensitive transcription factor EGR1 (Morawietz et al, 1999). Mechanical strain induces transcription of the cysteine-rich angiogenic inducer 61 (CYR61), a crucial gene for vascular development and repair in smooth muscle cells (Chaqour and Goppelt-Struebe, 2006). In addition, cyclic stretching of rat aortic smooth muscle cells has been shown to increase the protein expression of endothelin B receptor, which is involved in blood-pressure-dependent arterial remodeling.…”

Section: Blood Vesselsmentioning

confidence: 99%

Mechanosensitive mechanisms in transcriptional regulation

Mammoto

Ingber

2012

Journal of Cell Science

343

291

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SummaryTranscriptional regulation contributes to the maintenance of pluripotency, self-renewal and differentiation in embryonic cells and in stem cells. Therefore, control of gene expression at the level of transcription is crucial for embryonic development, as well as for organogenesis, functional adaptation, and regeneration in adult tissues and organs. In the past, most work has focused on how transcriptional regulation results from the complex interplay between chemical cues, adhesion signals, transcription factors and their co-regulators during development. However, chemical signaling alone is not sufficient to explain how three-dimensional (3D) tissues and organs are constructed and maintained through the spatiotemporal control of transcriptional activities. Accumulated evidence indicates that mechanical cues, which include physical forces (e.g. tension, compression or shear stress), alterations in extracellular matrix (ECM) mechanics and changes in cell shape, are transmitted to the nucleus directly or indirectly to orchestrate transcriptional activities that are crucial for embryogenesis and organogenesis. In this Commentary, we review how the mechanical control of gene transcription contributes to the maintenance of pluripotency, determination of cell fate, pattern formation and organogenesis, as well as how it is involved in the control of cell and tissue function throughout embryogenesis and adult life. A deeper understanding of these mechanosensitive transcriptional control mechanisms should lead to new approaches to tissue engineering and regenerative medicine. IntroductionTissue and organ architecture are constructed as a result of the complex orchestration of various cell types that exhibit specific behaviors (e.g. growth, differentiation, migration and apoptosis) in specific locations at precise times during embryogenesis. Transcriptional programs confer and maintain cellular identity and functions that are necessary for the maturation of embryonic cells into terminally differentiated tissues or organs, as well as for stem cell fate switching throughout adult life. These behaviors are regulated by turning genes on and off in a highly spatiotemporally controlled manner, and this process is mediated at the level of gene transcription through the interplay between RNA polymerase II, various transcription factors and their co-regulators (Box 1). Whereas most studies on transcriptional regulation have focused on genetic or chemical control mechanisms of transcription, recent work suggests that mechanical forces (Box 2) are equally important regulators of transcriptional control in embryonic and adult tissues. In this Commentary, we review these new insights into cellular mechanotransduction, and discuss how mechanical cues influence transcriptional regulation to govern organogenesis and to ensure tissue maintenance throughout adult life.

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Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins

Cited by 165 publications

References 93 publications

Pericellular fibronectin is required for RhoA-dependent responses to cyclic strain in fibroblasts

Pericellular fibronectin is required for RhoA-dependent responses to cyclic strain in fibroblasts

Up-Regulation of Connective Tissue Growth Factor in Endothelial Cells by the Microtubule-Destabilizing Agent Combretastatin A-4

Mechanosensitive mechanisms in transcriptional regulation

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