scholarly journals The Ternary Complex Factor Net Regulates Cell Migration through Inhibition of PAI-1 Expression

2005 ◽  
Vol 25 (24) ◽  
pp. 10853-10862 ◽  
Author(s):  
Gilles Buchwalter ◽  
Christian Gross ◽  
Bohdan Wasylyk
Keyword(s):  
Cell Migration ◽  
Ternary Complex ◽  
Target Genes ◽  
Serum Response Factor ◽  
Plasminogen Activator Inhibitor ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Serum Response ◽  
Ternary Complex Factor ◽  
Pai 1

ABSTRACT Net, Elk-1, and Sap-1 are members of the ternary complex factor (TCF) subfamily of Ets transcription factors. They form ternary complexes with serum response factor (SRF) on serum response elements of immediate early genes such as c-fos and egr-1 and mediate responses to growth factors and mitogen-activated protein kinase signaling. Although the TCFs have been extensively studied as intermediates in signaling cascades, surprisingly little is known about their different target genes and physiological functions. We report that Net homozygous mutant mouse embryonic fibroblasts have a defect in cell migration. This defect results at least in part from increased expression of plasminogen activator inhibitor type 1 (PAI-1), a serine protease inhibitor (serpin) that controls extracellular proteolysis and cell matrix adhesion. The defect in cell migration can be reverted by the addition of a PAI-1 blocking antibody. Net represses PAI-1 promoter activity and binds to a specific region of the promoter containing Ets binding sites in the absence of SRF. We conclude that Net is a negative regulator of PAI-1 expression and is thereby involved in cell migration.

Complexities in ETS-Domain Transcription Factor Function and Regulation: Lessons from the TCF (Ternary Complex Factor) Subfamily

2002 ◽  
Vol 30 (2) ◽  
pp. 1-9 ◽  
Author(s):  
A. D. Sharrocks
Keyword(s):  
Transcription Factor ◽  
Ternary Complex ◽  
Serum Response Factor ◽  
Mitogen Activated Protein Kinase ◽  
Functional Conservation ◽  
Transcriptional Regulatory ◽  
Mitogen Activated Protein ◽  
Ets Domain ◽  
Ternary Complex Factor

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

scholarly journals Ternary Complex Factor-Serum Response Factor Complex-Regulated Gene Activity Is Required for Cellular Proliferation and Inhibition of Apoptotic Cell Death

2004 ◽  
Vol 24 (23) ◽  
pp. 10340-10351 ◽  
Author(s):  
Elaine R. Vickers ◽  
Aneta Kasza ◽  
Isil Aksan Kurnaz ◽  
Anne Seifert ◽  
Leo A. H. Zeef ◽  
...  
Keyword(s):  
Cell Death ◽  
Ternary Complex ◽  
Serum Response Factor ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Gene Activity ◽  
Immediate Early ◽  
Response Factor ◽  
Serum Response ◽  
Ternary Complex Factor

ABSTRACT Members of the ternary complex factor (TCF) subfamily of the ETS-domain transcription factors are activated through phosphorylation by mitogen-activated protein kinases (MAPKs) in response to a variety of mitogenic and stress stimuli. The TCFs bind and activate serum response elements (SREs) in the promoters of target genes in a ternary complex with a second transcription factor, serum response factor (SRF). The association of TCFs with SREs within immediate-early gene promoters is suggestive of a role for the ternary TCF-SRF complex in promoting cell cycle entry and proliferation in response to mitogenic signaling. Here we have investigated the downstream gene regulatory and phenotypic effects of inhibiting the activity of genes regulated by TCFs by expressing a dominantly acting repressive form of the TCF, Elk-1. Inhibition of ternary complex activity leads to the downregulation of several immediate-early genes. Furthermore, blocking TCF-mediated gene expression leads to growth arrest and triggers apoptosis. By using mutant Elk-1 alleles, we demonstrated that these effects are via an SRF-dependent mechanism. The antiapoptotic gene Mcl-1 is identified as a key target for the TCF-SRF complex in this system. Thus, our data confirm a role for TCF-SRF-regulated gene activity in regulating proliferation and provide further evidence to indicate a role in protecting cells from apoptotic cell death.

scholarly journals Androgen-responsive Serum Response Factor target genes regulate prostate cancer cell migration

2013 ◽  
Vol 34 (8) ◽  
pp. 1737-1746 ◽  
Author(s):  
A. R. Verone ◽  
K. Duncan ◽  
A. Godoy ◽  
N. Yadav ◽  
A. Bakin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Target Genes ◽  
Serum Response Factor ◽  
Prostate Cancer Cell ◽  
Response Factor ◽  
Cancer Cell Migration ◽  
Serum Response

scholarly journals MAL and Ternary Complex Factor Use Different Mechanisms To Contact a Common Surface on the Serum Response Factor DNA-Binding Domain

2006 ◽  
Vol 26 (11) ◽  
pp. 4134-4148 ◽  
Author(s):  
Alexia-Ileana Zaromytidou ◽  
Francesc Miralles ◽  
Richard Treisman
Keyword(s):  
Dna Binding ◽  
Complex Formation ◽  
Ternary Complex ◽  
Serum Response Factor ◽  
Dna Bending ◽  
Binding Domain ◽  
Response Factor ◽  
Dna Binding Domain ◽  
Serum Response ◽  
Ternary Complex Factor

ABSTRACT The transcription factor serum response factor (SRF) interacts with its cofactor, MAL/MKL1, a member of the myocardin-related transcription factor (MRTF) family, through its DNA-binding domain. We define a seven-residue sequence within the conserved MAL B1 region essential and sufficient for complex formation. The neighboring Q-box sequence facilitates this interaction. The B1 and Q-box regions also have antagonistic effects on MAL nuclear import, but the residues involved are largely distinct. Both MAL and the ternary complex factor (TCF) family of SRF cofactors interact with a hydrophobic groove and pocket on the SRF DNA-binding domain. Unlike the TCFs, however, interaction of MAL with SRF is impaired by SRF αI-helix mutations that reduce DNA bending in the SRF-DNA complex. A clustered SRF αI-helix mutation strongly impairs MAL-SRF complex formation but does not affect DNA distortion in the MAL-SRF complex. MAL-SRF complex formation is facilitated by DNA binding. DNase I footprinting indicates that in the SRF-MAL complex MAL directly contacts DNA. These contacts, which flank the DNA sequences protected from DNase I by SRF, are required for effective MAL-SRF complex formation in gel mobility shift assays. We propose a model of MAL-SRF complex formation in which MAL interacts with SRF by the addition of a β-strand to the SRF DNA-binding domain β-sheet region, while SRF-induced DNA bending facilitates MAL-DNA contact.

scholarly journals Megakaryoblastic Leukemia 1, a Potent Transcriptional Coactivator for Serum Response Factor (SRF), Is Required for Serum Induction of SRF Target Genes

2003 ◽  
Vol 23 (18) ◽  
pp. 6597-6608 ◽  
Author(s):  
Bo Cen ◽  
Ahalya Selvaraj ◽  
Rebecca C. Burgess ◽  
Johann K. Hitzler ◽  
Zhigui Ma ◽  
...  
Keyword(s):  
Target Genes ◽  
Serum Response Factor ◽  
Gene Activation ◽  
Reporter Genes ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Response Factor ◽  
Megakaryoblastic Leukemia ◽  
Serum Response

ABSTRACT Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related transcription factor that we found strongly activated serum response element (SRE)-dependent reporter genes through its direct binding to serum response factor (SRF). The c-fos SRE is regulated by mitogen-activated protein kinase phosphorylation of ternary complex factor (TCF) but is also regulated by a RhoA-dependent pathway. The mechanism of this pathway is unclear. Since MKL1 (also known as MAL, BSAC, and MRTF-A) is broadly expressed, we assessed its role in serum induction of c-fos and other SRE-regulated genes with a dominant negative MKL1 mutant (DN-MKL1) and RNA interference (RNAi). We found that DN-MKL1 and RNAi specifically blocked SRE-dependent reporter gene activation by serum and RhoA. Complete inhibition by RNAi required the additional inhibition of the related factor MKL2 (MRTF-B), showing the redundancy of these factors. DN-MKL1 reduced the late stage of serum induction of endogenous c-fos expression, suggesting that the TCF- and RhoA-dependent pathways contribute to temporally distinct phases of c-fos expression. Furthermore, serum induction of two TCF-independent SRE target genes, SRF and vinculin, was nearly completely blocked by DN-MKL1. Finally, the RBM15-MKL1 fusion protein formed by the t(1;22) translocation of acute megakaryoblastic leukemia had a markedly increased ability to activate SRE reporter genes, suggesting that its activation of SRF target genes may contribute to leukemogenesis.

scholarly journals The pruned gene encodes the Drosophila serum response factor and regulates cytoplasmic outgrowth during terminal branching of the tracheal system

Development ◽  
1996 ◽  
Vol 122 (5) ◽  
pp. 1353-1362 ◽  
Author(s):  
K. Guillemin ◽  
J. Groppe ◽  
K. Ducker ◽  
R. Treisman ◽  
E. Hafen ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Ternary Complex ◽  
Serum Response Factor ◽  
Response Factor ◽  
Loss Of Function ◽  
Tracheal System ◽  
Expression Of Genes ◽  
Serum Response ◽  
Cytoplasmic Processes ◽  
Ternary Complex Factor

We identified a Drosophila gene, pruned, that regulates formation of the terminal branches of the tracheal (respiratory) system. These branches arise by extension of long cytoplasmic processes from terminal tracheal cells towards oxygen-starved tissues, followed by formation of a lumen within the processes. The pruned gene is expressed in terminal cells throughout the period of terminal branching. pruned encodes the Drosophila homologue of serum response factor (SRF), which functions with an ETS domain ternary complex factor as a growth-factor-activated transcription complex in mammalian cells. In pruned loss of function mutants, terminal cells fail to extend cytoplasmic projections. A constitutively activated SRF drives formation of extra projections that grow out in an unregulated fashion. An activated ternary complex factor has a similar effect. We propose that the Drosophila SRF functions like mammalian SRF in an inducible transcription complex, and that activation of this complex by signals from target tissues induces expression of genes involved in cytoplasmic outgrowth.

scholarly journals Phosphorylation-dependent formation of a quaternary complex at the c-fos SRE.

1996 ◽  
Vol 16 (3) ◽  
pp. 1094-1102 ◽  
Author(s):  
H Gille ◽  
M Kortenjann ◽  
T Strahl ◽  
P E Shaw
Keyword(s):  
Ternary Complex ◽  
Serum Response Factor ◽  
Multicomponent Complex ◽  
Intermolecular Association ◽  
Quaternary Complex ◽  
In Vivo Footprinting ◽  
Serum Response ◽  
Ternary Complex Factor

The rapid and transient induction of the human proto-oncogene c-fos in response to a variety of stimuli depends on the serum responses element (SRE). In vivo footprinting experiments show that this promoter element is bound by a multicomponent complex including the serum response factor (SRF) and a ternary complex factor such as Elk-1. SRF is thought to recruit a ternary complex factor monomer into an asymmetric complex. In this report, we describe a quaternary complex over the SRE which, in addition to an SRF dimer, contains two Elk-1 molecules. Its formation at the SRE is strictly dependent on phosphorylation of S-383 in the Elk-1 regulatory domain and appears to involve a weak intermolecular association between the two Elk-1 molecules. The influence of mutations in Elk-1 on quaternary complex formation in vitro correlates with their effect on the induction of c-fos reporter expression in response to mitogenic stimuli in vivo.

Abstract 188: Selective Inhibition of Vascular Smooth Muscle Cell Migration by Targeting Plasminogen Activator Inhibitor-1

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Neha Goyal ◽  
Zhen Weng ◽  
Philip Fish ◽  
Tammy Strawn ◽  
Samantha Myears ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Plasminogen Activator ◽  
Intimal Hyperplasia ◽  
Differential Effect ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Introduction: Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of mammalian plasminogen activators and an important regulator of cell migration. We have shown that tiplaxtinin, a small molecule, specific inhibitor of PAI-1, inhibits intimal hyperplasia in a murine vein graft model. However, little is known about the effects of pharmacological inhibition of PAI-1 on vascular cell migration under physiologically relevant conditions. Methods: We studied the effects of tiplaxtinin on migration of smooth muscle cells (SMCs) and endothelial cells (ECs). Results: Tiplaxtinin significantly inhibited migration of murine SMCs through 3-dimensional (3-D) collagen matrix in a concentration-dependent manner. Tiplaxtinin did not inhibit SMC proliferation, and it did not inhibit migration of PAI-1-deficient SMCs, suggesting that tiplaxtinin’s effect on SMCs was non-toxic and PAI-1-dependent. The anti-migratory effect of tiplaxtinin on SMCs was preserved in collagen 3-D matrix containing vitronectin and other extracellular matrix molecules, further supporting the physiological significance of the effect. In contrast to SMCs, tiplaxtinin did not inhibit migration of human aortic ECs in vitro or murine ECs in vivo, the latter assessed in a murine carotid injury model. To study the basis for the differential effect of tiplaxtinin on SMCs vs. ECs, we compared expression of LDL receptor-related protein 1 (LRP1), a motogenic receptor for PAI-1, between cell types by RT-PCR and found that LRP1 gene expression was significantly lower in ECs than in SMCs. Furthermore, recombinant PAI-1 stimulated the migration of wild-type mouse embryonic fibroblasts (MEFs), but not LRP1-deficient MEFs. Conclusions: Tiplaxtinin, a pharmacological inhibitor of PAI-1, inhibits SMC migration under physiological conditions, while having no inhibitory effect on EC migration. The differential effect of PAI-1 inhibition on SMCs vs. ECs appears to be mediated by LRP1 and may be of clinical significance, as it is advantageous to prevent intimal hyperplasia by inhibiting SMC migration without inhibiting EC migration, which is key to preserving an intact, anti-thrombotic vascular endothelium.

Isolation and characterization of SRF accessory proteins

1993 ◽  
Vol 340 (1293) ◽  
pp. 325-332 ◽  
Keyword(s):  
Ternary Complex ◽  
Map Kinases ◽  
Serum Response Factor ◽  
Regulatory Element ◽  
Isolation And Characterization ◽  
Activation Of Transcription ◽  
Serum Response ◽  
Dna Binding Properties

Many genes which are regulated by growth factors contain a common regulatory element, the serum response element (SRE). Activation of transcription by the SRE involves a ternary complex formed between a ubiquitous factor, serum response factor (SRF), and a second protein, p62/TCF. We used a yeast genetic screen to isolate cDNAs encoding a protein, SAP-1, with the DNA binding properties of p62/TCF. The SAP-1 sequence contains three regions of homology to the previously uncharacterized Elk-1 protein, which also acts as an SRF accessory protein. Only two of these regions are required for cooperative interactions with SRF in the ternary complex. The third contains several conserved sites for the MAP kinases, whose activity is regulated in response to growth factor stimulation. We discuss the potential role of these proteins in regulation of the c-fos SRE.

scholarly journals Histone Deacetylase Inhibitor Impairs Plasminogen Activator Inhibitor-1 Expression via Inhibiting TNF-α-Activated MAPK/AP-1 Signaling Cascade

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Wei-Lin Chen ◽  
Joen-Rong Sheu ◽  
Che-Jen Hsiao ◽  
Shih-Hsin Hsiao ◽  
Chi-Li Chung ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Histone Deacetylases ◽  
Plasminogen Activator Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Hdac Inhibition ◽  
Plasminogen Activator Inhibitor 1 ◽  
Hdac Activity ◽  
Mitogen Activated Protein ◽  
Activator Inhibitor ◽  
Pai 1

Tumor necrosis factor-(TNF-)-αupregulates plasminogen activator inhibitor-(PAI-) 1 expression in pleural mesothelial cells (PMCs), contributing to fibrin deposition and pleural fibrosis. Histone deacetylases (HDACs) have been found implicated in fibrogenesis. However, the roles of TNF-αor HDAC in the regulation of PAI-1 expression have not been well investigated. We aimed to examine the effects and mechanisms of HDAC inhibition on TNF-α-induced PAI-1 expression in human PMCs. MeT-5A human PMCs were treated with TNF-αin the presence or absence of them-carboxycinnamic acid bishydroxamide (CBHA), an HDAC class II inhibitor, and the HDAC activity, PAI-1 protein expression, mRNA, and activated signalings were analyzed. CBHA abrogated TNF-α-induced HDAC activity, PAI-1 protein and, mRNA expression in MeT-5A cells. Moreover, CBHA significantly enhanced mitogen-activated protein kinase phosphatase-(MKP-) 5/MKP-1 expression and inhibited p38/JNK activations, ATF2/c-Jun translocation, and PAI-1 promoter activity. Altogether, our data suggest that HDAC inhibition may abrogate TNF-α-activated MAPK/AP-1 signaling and PAI-1 expression in human PMCs. Given the antifibrotic effect through PAI-1 abrogation, CBHA may be utilized as a novel agent in the treatment of fibrotic diseases.

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