Tandem Sp1/Sp3 sites together with an Ets-1 site cooperate to mediate α11 integrin chain expression in mesenchymal cells

Lü, Ning; Heuchel, Rainer; Barczyk, Malgorzata; Zhang, Wanming; Gullberg, Donald

doi:10.1016/j.matbio.2005.10.002

Cited by 27 publications

(29 citation statements)

References 63 publications

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“…A role for Ets1 in the transcriptional regulation of a number of integrin subunits has been described, positioning Ets1 upstream of integrins [24,25,26,27]. The finding that motility induced by pGlcNAc is dependent both on integrins and Ets1 implies that Ets1 may be regulated downstream of integrins.…”

Section: Resultsmentioning

confidence: 99%

Poly-N-Acetyl Glucosamine Nanofibers Regulate Endothelial Cell Movement and Angiogenesis: Dependency on Integrin Activation of Ets1

et al. 2007

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Poly-N-acetyl glucosamine (pGlcNAc) nanofiber-derived materials effectively achieve hemostasis during surgical procedures. Treatment of cutaneous wounds with pGlcNAc in a diabetic mouse animal model causes marked increases in cell proliferation and angiogenesis. We sought to understand the effect of the pGlcNAc fibers on primary endothelial cells (EC) in culture and found that pGlcNAc induces EC motility. Cell motility induced by pGlcNAc fibers is blocked by antibodies directed against αVβ₃ and α₅β₁ integrins, both known to play important roles in the regulation of EC motility, in vitroand in vivo. pGlcNAc treatment activates mitogen-activated protein kinase and increases Ets1, vascular endothelial growth factor (VEGF) and interleukin 1 (IL-1) expression. pGlcNAc activity is not secondary to its induction of VEGF; inhibition of the VEGF receptor does not inhibit the pGlcNAc-induced expression of Ets1 nor does pGlcNAc cause the activation of VEGF receptor. Both dominant negative and RNA interference inhibition of Ets1 blocks pGlcNAc-induced EC motility. Antibody blockade of integrin results in the inhibition of pGlcNAc-induced Ets1 expression. These findings support the hypothesis that pGlcNAc fibers induce integrin activation which results in the regulation of EC motility and thus in angiogenesis via a pathway dependent on the Ets1 transcription factor and demonstrate that Ets1 is a downstream mediator of integrin activation.

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Section: Resultsmentioning

confidence: 99%

Poly-N-Acetyl Glucosamine Nanofibers Regulate Endothelial Cell Movement and Angiogenesis: Dependency on Integrin Activation of Ets1

et al. 2007

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“…The fact that an intact cytoskeleton is needed for the ␣11 up-regulation might indicate that such a mechanical stress-sensitive element also is present in the ITGA11 promoter. No obvious conserved canonical CArG-box is present in the 3-kb part of the promoter (30), so the involvement of CArG-boxes in the regulation of ␣11 is currently unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The medium containing plasmids and transfection reagent was then removed and replaced by fresh DMEM, 10% FBS, 1% Pest, and either the corresponding amounts of recombinant TGF-␤1 or conditioned medium from SV40 immortalized MEFs seeded in attached gels were added. After 24 h, luciferase and ␤-gal activities of duplicate samples for each condition were measured in two independent experiments as reported previously (30). Transfected cells that survived in selection medium (29) for 14 days were considered as stably transfected, further grown under selection medium, and seeded within collagen gels (supplemental Fig.…”

Section: Methodsmentioning

confidence: 99%

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The Fibroblast Integrin α11β1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation

Carracedo

Lü

Popova

et al. 2010

Journal of Biological Chemistry

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129

116

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Fibrotic tissue is characterized by an overabundance of myofibroblasts. Thus, understanding the factors that induce myofibroblast differentiation is paramount to preventing fibrotic healing. Previous studies have shown that mechanical stress derived from the integrin-mediated interaction between extracellular matrix and the cytoskeleton promotes myofibroblast differentiation. Integrin ␣11␤1 is a collagen receptor on fibroblasts. To determine whether ␣11␤1 can act as a mechanosensor to promote the myofibroblast phenotype, mouse embryonic fibroblasts and human corneal fibroblasts were utilized. We found that ␣11 mRNA and protein levels were up-regulated in mouse embryonic fibroblasts grown in attached three-dimensional collagen gels and conversely down-regulated in cells grown in floating gels. ␣11 up-regulation could be prevented by manually detaching the collagen gels or by cytochalasin D treatment. Furthermore, SB-431542, an inhibitor of signaling via ALK4, ALK5, and ALK7, prevented the up-regulation of ␣11 and the concomitant phosphorylation of Smad3 under attached conditions. In attached gels, TGF-␤1 was secreted in its inactive form but surprisingly not further activated, thus not influencing ␣11 regulation. However, inhibition of activin A attenuated the up-regulation of ␣11. To determine the role of ␣11 in myofibroblast differentiation, human corneal fibroblasts were transfected with small interfering RNA to ␣11, which decreased ␣-smooth muscle actin expression and myofibroblast differentiation. Our data suggest that ␣11␤1 is regulated by cell/matrix stress involving activin A and Smad3 and that ␣11␤1 regulates myofibroblast differentiation.

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“…Interestingly, in silico analysis of the mouse and human ␤3 integrin gene promoters (30, 31) (GenBank TM accession numbers AF026510 and AF02055, respectively) revealed considerable sequence homology across a 1.3-kb region upstream of the transcription start site and several conserved binding elements for Sp1 but not for Smad proteins. Recently, it has been demonstrated that cooperation between Sp1 and Smad proteins may represent a general regulatory mechanism for conferring the TGF␤1 inducibility of several genes, including ␤5, ␣5, and ␣11 integrins (13,20,32) and different types of collagen (33,34). In these studies the antibiotic mithramycin A selectively and efficiently reduced TGF␤-induced collagen and ␣11 integrin expression in mesenchymal cells via inhibition of Sp1 binding to the gene promoter.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway

Pechkovsky

Scaffidi

Hackett

et al. 2008

Journal of Biological Chemistry

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In response to transforming growth factor ␤1 (TGF␤) stimulation, fibroblasts modify their integrin repertoire and adhesive capabilities to certain extracellular matrix proteins. Although TGF␤ has been shown to increase the expression of specific ␣v integrins, the mechanisms underlying this are unknown. In this study we demonstrate that TGF␤1 increased both ␤3 integrin subunit mRNA and protein levels as well as surface expression of ␣v␤3 in human lung fibroblasts. TGF␤1-induced ␣v␤3 expression was strongly adhesion-dependent and associated with increased focal adhesion kinase and c-Src kinase phosphorylation. Inhibition of ␤3 integrin activation by the Arg-Gly-Asp tripeptide motif-specific disintegrin echistatin or ␣v␤3 blocking antibody prevented the increase in ␤3 but not ␤5 integrin expression. In addition, echistatin inhibited TGF␤1-induced p38 MAPK but not Smad3 activation. Furthermore, inhibition of the Src family kinases, but not focal adhesion kinase, completely abrogated TGF␤1-induced expression of ␣v␤3 and p38 MAPK phosphorylation but not ␤5 integrin expression and Smad3 activation. The TGF␤1-induced ␣v␤3 expression was blocked by pharmacologic and genetic inhibition of p38 MAPKbut not Smad2/3-, Sp1-, ERK-, phosphatidylinositol 3-kinase, and NF-B-dependent pathways. Our results demonstrate that TGF␤1 induces ␣v␤3 integrin expression via a ␤3 integrin-, c-Src-, and p38 MAPK-dependent pathway. These data identify a novel mechanism for TGF␤1 signaling in human lung fibroblasts by which they may contribute to normal and pathological wound healing.One of the key events in wound repair is the infiltration of fibroblasts from surrounding tissue to the extracellular matrix (ECM) 2 in which they proliferate and differentiate into myofibroblasts. Under normal conditions myofibroblasts play a crucial role in ECM deposition and subsequent wound contraction and then disappear as the fibrotic response diminishes and normal structure and function are achieved (1). However, their retention, uncontrolled proliferation, and excessive synthesis of ECM proteins represents a pathologic process that ultimately results in fibrosis (2). Both fibroblast proliferation and differentiation, as well as ECM protein synthesis, are profoundly influenced by growth factors such as TGF␤ as well as cell adhesion (3-6). Adhesion of cells to ECM is mediated by a family of transmembrane proteins known as integrins that are expressed on the cell surface as ␣/␤ heterodimers (7, 8). Importantly, integrins not only support cell attachment but also act in concert with receptors for several growth factors, including TGF␤, to regulate survival, migration, proliferation, and differentiation of fibroblastic, epithelial, and endothelial cells (reviewed in Refs. 7,8). Over the past few years a close relationship between ␣v integrins (recognizing RGD motif) and TGF␤ signaling pathways has been identified (9). These include activation of latent TGF␤ complexes by ␣v␤6 and ␣v␤8 integrins in airway epithelium (8, 10), augmented TGF␤ signaling by ␣v␤3 and ␣v...

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Tandem Sp1/Sp3 sites together with an Ets-1 site cooperate to mediate α11 integrin chain expression in mesenchymal cells

Cited by 27 publications

References 63 publications

Poly-N-Acetyl Glucosamine Nanofibers Regulate Endothelial Cell Movement and Angiogenesis: Dependency on Integrin Activation of Ets1

Poly-N-Acetyl Glucosamine Nanofibers Regulate Endothelial Cell Movement and Angiogenesis: Dependency on Integrin Activation of Ets1

The Fibroblast Integrin α11β1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation

Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway

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