Inducible Expression of Egr-1–Dependent Genes
1997; Lippincott Williams & Wilkins; Volume: 81; Issue: 4 Linguagem: Inglês
10.1161/01.res.81.4.457
ISSN1524-4571
AutoresLevon M. Khachigian, Tucker Collins,
Tópico(s)Genomics and Chromatin Dynamics
ResumoHomeCirculation ResearchVol. 81, No. 4Inducible Expression of Egr-1–Dependent Genes Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBInducible Expression of Egr-1–Dependent Genes A Paradigm of Transcriptional Activation in Vascular Endothelium Levon M. Khachigian and Tucker Collins Levon M. KhachigianLevon M. Khachigian From The Centre for Thrombosis and Vascular Research (L.M.K.), School of Pathology, The University of New South Wales, Sydney, Australia, and the Vascular Research Division (T.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. and Tucker CollinsTucker Collins From The Centre for Thrombosis and Vascular Research (L.M.K.), School of Pathology, The University of New South Wales, Sydney, Australia, and the Vascular Research Division (T.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. Originally published19 Oct 1997https://doi.org/10.1161/01.RES.81.4.457Circulation Research. 1997;81:457–461Throughout the vascular network, endothelium forms the continuous cellular interface between the circulating blood elements and the surrounding tissues. These cells provide a nonthrombogenic surface and a permeability barrier capable of modulating blood flow and vascular reactivity. As such, the integrity of the endothelium is a fundamental requirement for the maintenance of normal homeostasis. Injury to this lining and the subsequent inflammatory response are among the earliest cellular events in the pathogenesis of atherosclerosis.1 This can result in dramatic phenotypic changes that render otherwise quiescent endothelium adhesive and prothrombotic. Lesions of atherosclerosis and postangioplasty restenosis may develop under the influence of molecules inducibly expressed or simply released by activated or injured endothelium. Several lines of evidence over the last decade, based on ligand and receptor localization, overexpression, and infusion studies, have correlated PDGF with the development of vascular occlusive lesions. PDGF appears to play a regulatory role in the migratory, rather than proliferative, events associated with the response to arterial injury. PDGF expression is quite low in the quiescent vessel wall, but levels of the growth factor increase substantially after injury. This Mini Review will focus on the transcriptional mechanisms underlying inducible PDGF expression in vascular endothelium and smooth muscle cells, with particular emphasis on the role played by the early growth response gene product, Egr-1.Sp1 Mediates Basal PDGF Gene ExpressionThe vessel wall responds to a changing local environment by modulating the expression of specific sets of genes. Transcriptional activation in response to these signals involves the regulated assembly of multiprotein complexes on promoters. The promoter regions of the PDGF-A and PDGF-B genes have been characterized, and some of the regulatory sequences and transcriptional activators have been defined. In endothelial cells, 5′ deletion analysis of both promoters has determined that the minimal promoters consist of ≈100 bp.23 The zinc-finger transcription factor, Sp1, was the first endogenous nuclear factor found to interact with the PDGF-A promoter2 and PDGF-B promoter.3 Sp1 binds to consensus elements in the proximal PDGF-A promoter2 as well as to the 5′-CCACCC-3′ motif in the proximal PDGF-B promoter.34 Cotransfection and mutational studies revealed that the ability of Sp1 to bind is critical for basal expression driven by the PDGF-A2 and PDGF-B3 promoters in cultured cells, consistent with "housekeeping" roles for this factor reported elsewhere.5 In vivo footprinting indicates that the Sp1 site in the PDGF-B promoter is occupied by nuclear factor(s) in intact cells.6 Moreover, the proximal region of the PDGF-A promoter spanning the Sp1 site is sensitive to cleavage by S1 nuclease,7 consistent with the possibility that this region of the PDGF-A gene contains functional promoter elements. Sp1 and other factors may activate PDGF transcription and account for the low levels of expression observed in the resting vessel wall. Alternatively, they may serve as architectural proteins maintaining chromatin structure in such a way that enables these genes to be readily activated by inducible transcription factors. Whereas these findings implicate a regulatory role for the region immediately upstream from the TATA box of both genes, transcription factors associating with other elements in the gene may interact with transactivators in the core promoter and/or the basal complex to generate the authentic pattern of PDGF gene expression.Interplay of Egr-1 and Sp1 Over Promoter ElementsWe used PMA as a model agonist to explore the regulatory processes underlying the inducible expression of PDGF-A and PDGF-B in endothelial cells. PMA-response elements in both promoters were localized to the proximal Sp1 binding sites by 5′ deletion and transient transfection analysis.23 However, electrophoretic mobility shift assays and Northern blot analysis determined that Sp1 levels were unchanged in cells exposed to PMA.2 The Sp1 sites in the PDGF-A promoter overlap with a number of consensus elements for the structurally related transcription factor, Egr-1,8 also known as TIS8, krox-24, and NGFI-A. Egr-1 transcript and protein levels are low or undetectable in quiescent endothelial cells but are dramatically increased upon exposure to PMA.2 We showed that both recombinant and endogenous nuclear Egr-1 can bind to the PDGF-A PMA-response element.2 Transfection analysis indicates that this interaction is crucial for PMA-inducible PDGF-A promoter–dependent expression in endothelial cells.2 Similar strategies later revealed that Egr-1 binds to a cryptic element overlapping the Sp1 site in the PDGF-B promoter in cells exposed to PMA.9Since Sp1 occupies both PDGF promoters in resting cells, we hypothesized that inducible PDGF expression mediated by Egr-1 involves displacement of prebound Sp1 from their overlapping binding sites (Figure). Using recombinant proteins, we found that Egr-1 was capable of displacing prebound Sp1 from both PDGF promoters.29 Displacement was also observed in nuclear extracts of cells exposed to PMA.2910 Interplay of regulatory transcription factors may be a common theme in inducible gene expression. Displacement has been suggested to occur in endothelial cells exposed to the proinflammatory cytokine TNF-α. TNF-α stimulates the nuclear translocation of nuclear factor-κB p50-p65, which activates transcription after p50-p50 homodimers are displaced from common binding sites. p50 is constitutively expressed and cannot activate transcription by itself because it does not contain a transcriptional activation domain. Using the Egr-1/Sp1 paradigm, we explored the possibility that Egr-1 modulates PDGF-A expression in pathophysiologically-relevant settings.Egr-1 Is Activated by Multiple (Patho)physiological Stimuli and Plays a Positive Regulatory Role in the Inducible Expression of Several Endothelial GenesPDGF-A and PDGF-B are expressed at low or undetectable levels in the unmanipulated rat artery wall. Upon denudation of aortic endothelium, however, these genes are inducibly expressed at the wound edge.11 On the basis of our in vitro observations with PMA, we explored the possibility that Egr-1 might also be involved in the inducible expression of these genes in the injured vessel wall. In situ hybridization with en face preparations determined that the inducible expression of PDGF-A and PDGF-B is preceded by a dramatic and transient increase in Egr-1 transcripts at the same location.9 Nuclear runoff experiments revealed that Egr-1 is activated at the level of transcription in endothelium injured in vitro.9 Egr-1 induced by injury binds to the proximal PDGF-A and PDGF-B promoters and can displace Sp1 from both genes.9 This provided the first direct link between a transcription factor and a target gene in the context of vascular injury. Interestingly, several other genes, whose products influence chemotactic, proliferative, and thrombogenic events associated with vascular occlusive lesions, are targets of Egr-1. These include tissue factor, TGF-β1, and u-PA (Table). These genes, like both chains of PDGF, are expressed at the wound edge only after the transient appearance of Egr-1.9 In binding studies with recombinant proteins, we found that Sp1 could be displaced from the proximal promoters of each of these genes by Egr-1.9 Accordingly, competitive interactions between Egr-1 and Sp1 may be a common theme in the inducible expression of multiple pathophysiologically relevant genes in response to injury.The first smooth muscle cells to migrate from the media to the intima, a week or so after endothelial denudation in the rat artery, do so at the wound edge.12 Since "gentle" injury does not physically traumatize underlying smooth muscle,13 factors released by damaged endothelium may contribute to this paracrine chemotactic response. FGF-2 lacks a classic signal peptide for exocytotic secretion. Consequently, it is found preformed in endothelial and smooth muscle cells both in culture and in the artery wall. We hypothesized that inducible Egr-1 and PDGF expression following endothelial injury may be due to the release and local action of FGF-2. Exposure of endothelial cells to FGF-2 induced the expression and nuclear accumulation of Egr-1. Egr-1 bound to the proximal PDGF-A promoter before the inducible expression and secretion of PDGF-AA. Preincubation of endothelial monolayers with neutralizing antibodies to FGF-2 profoundly inhibited the induction of Egr-1 and its interaction with the PDGF-A promoter. Thus, endogenous FGF-2 contributes to the activation of Egr-1 upon endothelial injury (L.M. Khachigian, unpublished data, 1997). PDGF synthesized and secreted by endothelial cells may, in turn, induce further growth factor expression in smooth muscle cells via Egr-1/Sp1 interplay in a paracrine manner.10The nonrandom spatial distribution of early atherosclerotic lesions in humans and animal models and the positive correlation of these lesions with disturbed blood flow patterns14 has suggested that local hemodynamic factors could influence the normal structure and function of endothelium in the vessel wall.15 Alterations in blood flow and shear stress in surgically manipulated baboon arteries result in elevated PDGF-A mRNA expression and protein levels in the endothelium.16 In collaborative studies with Dr Michael Gimbrone, Jr, and colleagues (Dewey et al17 ), we used a well-characterized in vitro mechanical model to apply physiological levels of laminar shear stress (10 dyne/cm2) to endothelial monolayers and found that PDGF-A mRNA is also inducibly expressed in this setting.18 Nuclear runoff studies determined that this increase is mediated, at least in part, at the transcriptional level.18 Deletion analysis of the PDGF-A promoter defined the Sp1/Egr-1 binding site as an SSRE. Although Egr-1 transcript levels increased in endothelial cells exposed to shear stress, Sp1 levels were not significantly altered. Egr-1 protein translocates to the nucleus minutes after the application of shear, where it binds to the PDGF-A SSRE after displacing Sp1 (Figure). This interaction is crucial for shear-inducible PDGF-A promoter–dependent expression.18 Taken together, these findings demonstrate that Egr-1 is activated in endothelial cells exposed multiple stimuli and may in turn be a pluripotent inducer of other genes. Recent evidence suggests that shear-inducible tissue factor expression also involves the interplay of Egr-1 and Sp1 in the proximal promoter,19 although Sp1 hyperphosphorylation has also been implicated in the induction of this gene.20Authentic Targets for Egr-1: Lessons From Mice With a Targeted Mutation in Egr-1Establishing authentic biological roles for Egr-1 is a key unresolved issue. One approach to this challenge is a loss-of-function strategy in which mice are produced with a targeted mutation in the Egr-1 gene. Generation of mice carrying a null mutation in the Egr-1 gene by Dr Jeff Milbrandt and colleagues (Lee et al21 ) have provided a valuable research tool to gain important insights into the functions of Egr-1 in vivo. Although no observable developmental or behavioral defects have been reported to date,21 female homozygotes are incapable of reproduction.22 These mice have low or undetectable levels of LH-β mRNA and protein, whereas levels of follicle-stimulating hormone-β and prolactin or receptors for gonadotropin-releasing hormone and type II activin are not attenuated. The lack of LH-β expression in knockout mice is due to inactivity of the LH-β promoter by virtue of a single conserved Egr-1 binding site in the proximal region.22 Analysis of these animals may provide direct links between Egr-1 and specific target genes. It will be interesting to determine whether PDGF-A, PDGF-B, TGF-β1, u-PA, and tissue factor activation at the wound edge after endothelial denudation is compromised in this animal model. Although provocative if this analysis suggests a relationship, phenotypic analysis of these mice is complicated by the potential functional redundancy contributed by related members of the Egr family.Activation of Egr-1 ItselfThe intracellular signaling pathways underlying the inducible expression of Egr-1 involve cooperative interactions between SRF and TCFs, such as Elk-1 and SAP-1, at SREs in the Egr-1 promoter. Our present knowledge on these regulatory processes is based mainly on insights obtained from studies on the c-fos promoter,23 where a quaternary complex composed of two molecules of TCF and two molecules of SRF forms over the SRE.24 Elk-1 and SAP-1 are both substrates of phosphorylation by members of the mitogen-activated kinase superfamily, JNK and ERK.25 ERK-1/2 and JNK-1 are rapidly activated in endothelial cells after mechanical injury or upon exposure to FGF-2 or PMA (L.M. Khachigian, unpublished data, 1997). These kinases are also activated in endothelial cells exposed to physiological levels of fluid shear stress.2627 Thus, it appears that diverse biochemical and fluid biomechanical stimuli activate Egr-1 and Egr-1–dependent expression by triggering distinct signaling pathways that converge at the Egr-1 promoter (Figure).Negative Regulation of PDGF and Egr-1The PDGF-A and PDGF-B promoters are also subject to negative transcriptional regulation. The Wilms' tumor suppressor gene encodes a zinc-finger DNA binding protein, WT-1, that interacts with the Egr-1/Sp1 binding site in the PDGF-A promoter.2829 Transient cotransfection studies have determined that WT-1 serves as a potent repressor of PDGF-A transcription.2829 Although it is not known whether the inhibitory activity of WT-1 involves the displacement of prebound Sp1 or Egr-1 from the promoter in intact cells, we have shown this to be the case with recombinant proteins (L.M. Khachigian and T. Collins, unpublished data, 1997). Interestingly, WT-1 does not appear to bind to the PDGF-B promoter. Whether an inverse proportional relationship exists between the expression of PDGF-A and WT-1 in vascular cells is not yet known. Varying levels of PDGF-A expression in different cell types, or the magnitude and duration of its induction, may be influenced by the constitutive or mutable expression of transcriptional repressors, such as WT-1.Two corepressors of Egr-1, NAB130 and NAB2,31 have been identified. These factors inhibit the activity of Egr-1 by direct protein-protein interactions, supporting earlier findings that deletion of certain peptide regions in the Egr-1 molecule actually increases transcriptional activity by ≥10-fold.3233 Whereas NAB1 is constitutively expressed, NAB2 is stimulated by known inducers of Egr-1, such as serum and growth factors. This raises the intriguing possibility that NAB-like factors mediate the postinduction transcriptional repression of PDGF and other Egr-1–dependent genes.The processes of cell movement and proliferation following mechanical injury are preceded by acute changes in gene expression. Multiple studies have correlated vascular remodeling with the inducible expression of PDGF and other genes. Although we have only begun to dissect the transcriptional mechanisms mediating these events, this Mini Review illustrates that positive transcriptional activation by Egr-1 may be a key to the inducible expression of PDGF and perhaps multiple other pathophysiologically relevant genes in cells of the vessel wall.Selected Abbreviations and AcronymsERK=extracellular regulated kinaseFGF-2=fibroblast growth factor-2JNK=c-Jun N-terminal kinaseLH-β=luteinizing hormone-βPDGF=platelet-derived growth factorPMA=phorbol 12-myristate 13-acetateSRE=serum response elementSRF=ternary complex factorsSSRE=shear-stress response elementTCF=ternary complex factorTGF-β1=transforming growth factor-β1TNF-α=tumor necrosis factor-αu-PA=urokinase-type plasminogen activatorDownload figureDownload PowerPoint Figure 1. Model of the cascade of molecular events underlying the inducible expression of Egr-1–dependent genes in vascular endothelial cells. Multiple extracellular stimuli activate phosphorylation-dependent signaling pathways, which converge at the Egr-1 promoter (see text). Upon synthesis, Egr-1 translocates to the nucleus and activates gene expression after displacing Sp1. Table 1. Targets of Transcriptional Regulation by Egr-1 in Vascular PathobiologyClass of MoleculeGeneReferenceGrowth factors and hormonesPDGF-A2, 10, 18PDGF-B9TGF-β19, 34FGF-235LH-β22LipoproteinsApolipoprotein AI36CytokinesTNF-α37Adhesion moleculesICAM-138CD4439Coagulation componentsTissue factor19, 40u-PA9, 41Leukotriene synthesis5-Lipoxygenase42Transcriptional repressorp5343ICAM-1 indicates intercellular adhesion molecule-1.Dr Khachigian holds an R. Douglas Wright Research Fellowship from the National Health and Medical Research Council of Australia, and Dr Collins is supported by grants RO1 HL-35716, HL-45462, and PO1 HL-36028 from the National Institutes of Health. The authors regret that space limitations have precluded a comprehensive citation of all relevant primary publications.FootnotesCorrespondence to Levon M. Khachigian, PhD, The Centre for Thrombosis and Vascular Research, School of Pathology, The University of New South Wales, Sydney NSW 2052, Australia. E-mail [email protected] References 1 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature.1993; 362:801-809.CrossrefMedlineGoogle Scholar2 Khachigian LM, Williams AJ, Collins T. Interplay of Sp1 and Egr-1 in the proximal PDGF-A promoter in cultured vascular endothelial cells. J Biol Chem.1995; 270:27679-27686.CrossrefMedlineGoogle Scholar3 Khachigian LM, Fries JWU, Benz MW, Bonthron DT, Collins T. 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