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 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 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 Serum Response Factor Regulates Immediate Early Host Gene Expression in Toxoplasma gondii-Infected Host Cells

PLoS ONE ◽  
2011 ◽  
Vol 6 (3) ◽  
pp. e18335 ◽  
Author(s):  
Mandi Wiley ◽  
Crystal Teygong ◽  
Eric Phelps ◽  
Jay Radke ◽  
Ira J. Blader
Keyword(s):  
Gene Expression ◽  
Toxoplasma Gondii ◽  
Serum Response Factor ◽  
Host Gene ◽  
Host Cells ◽  
Immediate Early ◽  
Infected Host ◽  
Response Factor ◽  
Host Gene Expression ◽  
Serum Response

scholarly journals Combinatorial Expression of GATA4, Nkx2-5, and Serum Response Factor Directs Early Cardiac Gene Activity

2002 ◽  
Vol 277 (28) ◽  
pp. 25775-25782 ◽  
Author(s):  
Jorge L. Sepulveda ◽  
Spiros Vlahopoulos ◽  
Dinakar Iyer ◽  
Narasimhaswamy Belaguli ◽  
Robert J. Schwartz
Keyword(s):  
Serum Response Factor ◽  
Gene Activity ◽  
Response Factor ◽  
Cardiac Gene ◽  
Serum Response ◽  
Combinatorial Expression

scholarly journals Ανάλυση της λειτουργίας των ογκοπρωτεϊνών AP-1 και Ets στην επαγώμενη ρύθμιση γονιδίων-στόχων από μιτωτικά σήματα φυσιολογικών και καρκινικών κυττάρων

2002 ◽  
Author(s):  
Ελένη Ψυχάρη
Keyword(s):  
Ternary Complex ◽  
Serum Response Factor ◽  
Epithelial Mesenchymal Transition ◽  
High Mobility ◽  
High Mobility Group ◽  
Response Factor ◽  
Response Element ◽  
Mesenchymal Transition ◽  
High Mobility Group Proteins ◽  
Serum Response

Η πρωτεΐνη SRF (Serum Response Factor) είναι ένας μεταγραφικός παράγοντας, ο οποίος ρυθμίζει τη μεταγραφή πολλών πρώιμα εκφρασμένων γονιδίων, που σχετίζονται με τον κυτταρικό πολλαπλασιασμό, τη διαφοροποίηση και την ανάπτυξη. Σε αυτή την κατηγορία γονιδίων ανήκει το πρωτο-ογκογονίδιο c-fos. Στον υποκινητή του c-fos και πιο συγκεκριμένα στο στοιχείο SRE (Serum Response Element), που θεωρείται και το σημαντικότερο για τη μεταγραφή του, προσδένονται οι μεταγραφικοί παράγοντες SRF και TCFs (Ternary Complex Factors). Η οικογένεια των μεταγραφικών παραγόντων TCFs περιλαμβάνει τις πρωτεΐνες Elk-1, SAP1a και SAP-2/Erp/Net. Οι πρωτεΐνες αυτές προσδένονται στο DNA στη χαρακτηριστική αλληλουχία ets (GAA), αλληλεπιδρούν με τον SRF και ενεργοποιούνται από το ογκογονίδιο ras μέσω των MAP κινασών. Η πρωτεΐνη SRF προσδένεται στη χαρακτηριστική αλληλουχία GG(AT)6CC και φωσφορυλιώνεται κυρίως από την κασεϊνική κινάση II, γεγονός που αυξάνει τη δυνατότητα πρόσδεσής της στο DNA. Τελευταία έχουν προταθεί διάφοροι μηχανισμοί ενεργοποίησης της πρωτεΐνης SRF, δύο από τους οποίους σχετίζονται είτε με το σήμα της RhoA GΤΡάσης, ή με την ομάδα πρωτεϊνών υψηλής κινητικότητας (High Mobility Group Proteins, HMG-ls), που αυξάνουν την ικανότητα πρόσδεσής του SRF στο DNA και έτσι ενισχύεται η μεταγραφή των γονιδίων-στόχων. Στα πειράματα μας έχει χρησιμοποιηθεί ένα πολυσταδιακό σύστημα καρκινογένεσης της επιδερμίδας του ποντικού. Το σύστημα αυτό αποτελείται από αθανατοποιημένες φυσιολογικές έως πλήρως μεταστατικές κυτταρικές σειρές, οι οποίες έχουν προέλθει από κατεργασία της επιδερμίδας ποντικών με χημικά καρκινογόνο (DMBA, ΤΡΑ). Οι ουσίες αυτές επιφέρουν γενετικές αλλοιώσεις (με πιο χαρακτηριστικές μία σημειακή μετάλλαξη στο ογκογονίδιο ras και απώλεια του ογκοκατασταλτικού γονιδίου p53), που έχουν ως συνέπεια τη δημιουργία πλακώδους (επιθηλιακού) ή ατρακτοειδούς (μεσεγχυματικού) φαινοτύπου στις καρκινικές κυτταρικές σειρές. Σε αυτό το κυτταρικό σύστημα προσπαθήσαμε να διερευνήσουμε το ρόλο του μεταγραφικού παράγοντα SRF κατά την καρκινογένεση. Τα αποτελέσματά μας έδειξαν ότι ο SRF συμμετέχει στην εξέλιξη του καρκίνου και συγκεκριμένα στην επιθηλιακή-μεσεγχυματική μετάβαση (epithelial-mesenchymal transition, ΕΜΤ) των καρκινικών κυττάρων. Βρέθηκε ότι η ενεργότητα του SRF συσχετίζεται με την ενεργοποίηση της RhoA και τον αυξημένο σχηματισμό ινιδίων stress ακτίνης, στα καρκινικά κύτταρα με ατρακτοειδή φαινότυπο. Επίσης, στα καρκινικά κύτταρα, οι δομικές πρωτεΐνες HMG-I αυξάνουν την πρόσδεση του SRF στο SRE, συμμετέχοντας έτσι στην ενεργοποίηση του SRF. Αποτέλεσμα της δράσης αυτών των μηχανισμών ρύθμισης του SRF είναι η αύξηση της επαγωγής της μεταγραφής μέσω του στοιχείου SRE και κατά συνέπεια η μεταγραφική ενεργοποίηση γονιδίων-στόχων του SRF, όπως το c-fos. Επιπλέον, σε αυτή την εργασία εξετάστηκε ο μηχανισμός της μεταγραφικής ενεργοποίησης μέσω της πρωτεΐνης c-Jun. Συγκεκριμένα, έγινε ανάλυση της αλληλεπίδρασης της πρωτεΐνης c-Jun με το γενικό μεταγραφικό παράγοντα TFIID. Με πειράματα σε κύτταρα COS, βρέθηκε ότι υπάρχει φυσική αλληλεπίδραση των πρωτεϊνών c-Jun και hTAFII55 και συνεργασία μεταξύ τους στην μεταγραφική ενεργοποίηση γονιδίων-στόχων.

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.

scholarly journals Serum Response Factor-GATA Ternary Complex Required for Nuclear Signaling by a G-Protein-Coupled Receptor

2001 ◽  
Vol 21 (4) ◽  
pp. 1036-1044 ◽  
Author(s):  
Steves Morin ◽  
Pierre Paradis ◽  
Anne Aries ◽  
Mona Nemer
Keyword(s):  
G Protein ◽  
Ternary Complex ◽  
Serum Response Factor ◽  
Biologically Active ◽  
Specific Response ◽  
Response Factor ◽  
Tissue Specific ◽  
Gata Factors ◽  
G Protein Coupled ◽  
Serum Response

ABSTRACT Endothelins are a family of biologically active peptides that are critical for development and function of neural crest-derived and cardiovascular cells. These effects are mediated by two G-protein-coupled receptors and involve transcriptional regulation of growth-responsive and/or tissue-specific genes. We have used the cardiac ANF promoter, which represents the best-studied tissue-specific endothelin target, to elucidate the nuclear pathways responsible for the transcriptional effects of endothelins. We found that cardiac-specific response to endothelin 1 (ET-1) requires the combined action of the serum response factor (SRF) and the tissue-restricted GATA proteins which bind over their adjacent sites, within a 30-bp ET-1 response element. We show that SRF and GATA proteins form a novel ternary complex reminiscent of the well-characterized SRF-ternary complex factor interaction required for transcriptional induction of c-fos in response to growth factors. In transient cotransfections, GATA factors and SRF synergistically activate atrial natriuretic factor and other ET-1-inducible promoters that contain both GATA and SRF binding sites. Thus, GATA factors may represent a new class of tissue-specific SRF accessory factors that account for muscle- and other cell-specific SRF actions.

scholarly journals Protein Kinase Cδ Blocks Immediate-Early Gene Expression in Senescent Cells by Inactivating Serum Response Factor

2004 ◽  
Vol 24 (16) ◽  
pp. 7298-7311 ◽  
Author(s):  
Keith Wheaton ◽  
Karl Riabowol
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Serum Response Factor ◽  
Immediate Early Gene ◽  
Early Gene ◽  
Immediate Early ◽  
Response Factor ◽  
Serum Response

ABSTRACT Fibroblasts lose the ability to replicate in response to growth factors and become unable to express growth-associated immediate-early genes, including c-fos and egr-1, as they become senescent. The serum response factor (SRF), a major transcriptional activator of immediate-early gene promoters, loses the ability to bind to the serum response element (SRE) and becomes hyperphosphorylated in senescent cells. We identify protein kinase C delta (PKCδ) as the kinase responsible for inactivation of SRF both in vitro and endogenously in senescent cells. This is due to a higher level of PKCδ activity as cells age, production of the PKCδ catalytic fragment, and its nuclear localization in senescent but not in low-passage-number cells. The phosphorylation of T160 of SRF by PKCδ in vitro and in vivo led to loss of SRF DNA binding activity. Both the PKCδ inhibitor rottlerin and ectopic expression of a dominant negative form of PKCδ independently restored SRE-dependent transcription and immediate-early gene expression in senescent cells. Modulation of PKCδ activity in vivo with rottlerin or bistratene A altered senescent- and young-cell morphology, respectively. These observations support the idea that the coordinate transcriptional inhibition of several growth-associated genes by PKCδ contributes to the senescent phenotype.

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