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1
Harada, Hiroaki, Vibha N. Lama, Linda N. Badri, Takashi Ohtsuka, Danica Petrovic-Djergovic, Hui Liao, Yasushi Yoshikawa, Koichiro Iwanaga, Chris L. Lau, and David J. Pinsky. "Early growth response gene-1 promotes airway allograft rejection." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 1 (July 2007): L124—L130. http://dx.doi.org/10.1152/ajplung.00285.2006.
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Chronic airway rejection, characterized by lymphocytic bronchitis, epithelial cell damage, and obliterative bronchiolitis (OB), limits long-term survival after lung transplantation. The transcription factor early growth response gene-1 (Egr-1) induces diverse inflammatory mediators, some involved in OB pathogenesis. An orthotopic mouse tracheal transplant model was used to determine whether Egr-1 promotes development of airway allograft rejection. Significantly higher Egr-1 mRNA levels were seen in allografts (3.2-fold increase vs. isografts, P = 0.012). Allografts revealed thickening of epithelial and subepithelial airway layers (51 ± 4% luminal encroachment for allografts vs. 20 ± 3% for isografts, P < 0.0001) marked by significant lymphocytic infiltration. Absence of the Egr-1 gene in donor (but not recipient) tissue resulted in significant reduction in luminal narrowing (34 ± 4%, P = 0.0001) with corresponding diminution of T cell infiltration. Egr-1 null allografts exhibited a striking reduction in inducible nitric oxide synthase (iNOS) expression. Effector cytokines previously implicated in OB pathogenesis with known Egr-1 promoter motifs (IL-1β and JE/monocyte chemoattractant protein-1) were reduced in Egr-1 null allografts. These data suggest a paradigm wherein local induction of Egr-1 in tracheal allografts drives expression of inflammatory mediators responsible for lymphocyte recruitment and tissue destruction characteristic of airway rejection.
2
Suehiro, Jun-ichi, Takao Hamakubo, Tatsuhiko Kodama, William C. Aird, and Takashi Minami. "Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3." Blood 115, no. 12 (March 25, 2010): 2520–32. http://dx.doi.org/10.1182/blood-2009-07-233478.
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Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis, tumor growth, and sepsis. Endothelial cell activation, in turn, is mediated primarily at the level of gene transcription. Here, we show that in response to several activation agonists, including vascular endothelial growth factor (VEGF), tumor necrosis factor-α, and thrombin, endothelial cells demonstrate rapid and profound induction of the early growth response (Egr) genes egr-1 and egr-3. In VEGF-treated endothelial cells, induction of Egr-3 was far greater and more prolonged compared with Egr-1. VEGF-mediated stimulation of Egr-3 involved the inducible binding of NFATc, serum response factor, and CREB to their respective consensus motifs in the upstream promoter region of Egr-3. Knockdown of Egr-3 markedly impaired VEGF-mediated proliferation, migration, and tube formation of endothelial cells and blocked VEGF-induced monocyte adhesion. Egr-3 knockdown abrogated VEGF-mediated vascular outgrowth from ex vivo aortic rings and attenuated Matrigel plug vascularization and melanoma tumor growth in vivo. Together, these findings suggest that Egr-3 is a critical determinant of VEGF signaling in activated endothelial cells. Thus, Egr-3 represents a potential therapeutic target in VEGF-mediated vasculopathic diseases.
3
Tsai, Jo C., Lixin Liu, Jie Zhang, Katherine C. Spokes, James N. Topper, and William C. Aird. "Epidermal growth factor induces Egr-1 promoter activity in hepatocytes in vitro and in vivo." American Journal of Physiology-Gastrointestinal and Liver Physiology 281, no. 5 (November 1, 2001): G1271—G1278. http://dx.doi.org/10.1152/ajpgi.2001.281.5.g1271.
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Early growth response-1 (Egr-1) is a transcription factor that couples short-term changes in the extracellular milieu to long-term changes in gene expression. Under in vitro conditions, the Egr-1 gene has been shown to respond to many extracellular signals. In most cases, these findings have not been extended to the in vivo setting. The goal of the present study was to explore the role of epidermal growth factor (EGF) in mediating Egr-1 expression in hepatocytes under both in vitro and in vivo conditions. In HepG2 cells, Egr-1 protein and mRNA were upregulated in the presence of EGF. In stable transfections of HepG2 cells, a 1,200-bp Egr-1 promoter contained information for EGF response via a protein kinase C-independent, mitogen-activated protein kinase-dependent signaling pathway. A promoter region containing the two most proximal serum response elements was sufficient to transduce the EGF signal. In transgenic mice that carry the Egr-1 promoter coupled to the LacZ reporter gene, systemic delivery of EGF by intraperitoneal injection resulted in an induction of the endogenous Egr-1 gene and the Egr-1- lacZ transgene in hepatocytes. Together, these results suggest that the 1,200-bp promoter contains information for EGF response in hepatocytes both in vitro and in intact animals.
4
Tsai, Jo C., Lixin Liu, Jiazhen Guan, and William C. Aird. "The Egr-1 gene is induced by epidermal growth factor in ECV304 cells and primary endothelial cells." American Journal of Physiology-Cell Physiology 279, no. 5 (November 1, 2000): C1414—C1424. http://dx.doi.org/10.1152/ajpcell.2000.279.5.c1414.
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The early growth response (Egr)-1 transcription factor serves to couple changes in the extracellular environment to alterations in gene expression. An understanding of the mechanisms that underlie Egr-1 gene regulation should provide important insights into how environmental signals are transduced by endothelial cells. The aim of the present study was to determine whether epidermal growth factor (EGF) induces Egr-1 expression in endothelial cells. In ECV304 cells, Egr-1 mRNA and protein levels were increased in response to EGF. In stable transfection assays, the 1,200-bp promoter of the mouse Egr-1 gene contained information for EGF response via a protein kinase C-independent, mitogen-activated protein kinase-dependent pathway. The endogenous Egr-1 gene was similarly responsive to EGF in primary human umbilical vein endothelial cells, human coronary artery endothelial cells, and rat fat pad endothelial cells, but not in bovine aortic endothelial cells, calf pulmonary artery endothelial cells, or PY-4-1 endothelial cells. Together, these results suggest that the Egr-1 gene is responsive to EGF in a subset of endothelial cells.
5
Bedadala, Gautam, Feng Chen, Robert Figliozzi, Matthew Balish, and Victor Hsia. "Construction and Characterization of Recombinant HSV-1 Expressing Early Growth Response-1." ISRN Virology 2014 (February 12, 2014): 1–7. http://dx.doi.org/10.1155/2014/629641.
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Early Growth response-1 (Egr-1) is a transcription factor that possesses a variety of biological functions. It has been shown to regulate HSV-1 gene expression and replication in different cellular environments through the recruitment of distinct cofactor complexes. Previous studies demonstrated that Egr-1 can be induced by HSV-1 infection in corneal cells but the level was lower compared to other cell types. The primary goal of this report is to generate a recombinant HSV-1 constitutively expressing Egr-1 and to investigate the regulation of viral replication in different cell types or in animals with Egr-1 overexpression. The approach utilized was to introduce Egr-1 into the BAC system containing complete HSV-1 (F) genome. To assist in the insertion of Egr-1, a gene cassette was constructed that contains the Egr-1 gene flanked by loxP sites. In this clone Egr-1 is expressed under control of CMV immediate-early promoter followed by another gene cassette expressing the enhanced green fluorescent protein (EGFP) under the control of the elongation factor 1α (EF-1 α) promoter. The constructed recombinant viruses were completed containing the Egr-1 gene within the viral genome and the expression was characterized by qRT-PCR and Western blot analyses. Our results showed that Egr-1 transcript and protein can be generated and accumulated upon infection of recombinant virus in Vero and rabbit corneal cells SIRC. This unique virus therefore is useful for studying the effects of Egr-1 during HSV-1 replication and gene regulation in epithelial cells and neurons.
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Abdel-Latif, M. M. M., H. J. Windle, K. A. Fitzgerald, Y. S. Ang, D. Ní Eidhin, M. Li-Weber, K. Sabra, and D. Kelleher. "Helicobacter pylori Activates the Early Growth Response 1 Protein in Gastric Epithelial Cells." Infection and Immunity 72, no. 6 (June 2004): 3549–60. http://dx.doi.org/10.1128/iai.72.6.3549-3560.2004.
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ABSTRACT The early growth response 1 (Egr-1) transcription factor is rapidly induced by various stimuli and is implicated in the regulation of cell growth, differentiation, and gene expression. The aim of this study was to examine the effect of Helicobacter pylori on the expression of Egr-1 and Egr-1-regulated genes in gastric epithelial AGS cells. Egr-1 expression was assayed by immunoblotting and electrophoretic mobility shift assays using H. pylori-stimulated AGS cells. Transient transfection experiments with promoter-reporter constructs of CD44, ICAM-1, and CD95L were used for expression studies. H. pylori induced the expression of Egr-1 in gastric epithelial cell lines in a dose-dependent manner, with the rapid kinetics that are typical of this class of transcription factors. Immunohistochemical studies of biopsies revealed that Egr-1 expression is more abundant in H. pylori-positive patients than in uninfected individuals. Reporter-promoter transfection studies indicated that Egr-1 binding is required for the H. pylori-induced transcriptional promoter activity of the CD44, ICAM-1, and CD95L (APO-1/Fas) constructs. The blocking of egr-1 with an antisense sequence prevented H. pylori-induced Egr-1 and CD44 protein expression. The MEK1/2 signaling cascade participates in H. pylori-mediated Egr-1 expression, but the p38 pathway does not. The data indicate that H. pylori induces Egr-1 expression in AGS cells in vitro and that the Egr-1 protein is readily detectable in biopsies from H. pylori-positive subjects. These observations suggest that H. pylori-associated Egr-1 expression may play a role, in part, in H. pylori-induced pathology.
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Eto, Kazuhiro, Varinderpal Kaur, and Melissa K. Thomas. "Regulation of Insulin Gene Transcription by the Immediate-Early Growth Response Gene Egr-1." Endocrinology 147, no. 6 (June 1, 2006): 2923–35. http://dx.doi.org/10.1210/en.2005-1336.
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Abstract Changes in extracellular glucose levels regulate the expression of the immediate-early response gene and zinc finger transcription factor early growth response-1 (Egr-1) in insulin-producing pancreatic β-cells, but key target genes of Egr-1 in the endocrine pancreas have not been identified. We found that overexpression of Egr-1 in clonal (INS-1) β-cells increased transcriptional activation of the rat insulin I promoter. In contrast, reductions in Egr-1 expression levels or function with the introduction of either small interfering RNA targeted to Egr-1 (siEgr-1) or a dominant-negative form of Egr-1 decreased insulin promoter activation, and siEgr-1 suppressed insulin gene expression. Egr-1 did not directly interact with insulin promoter sequences, and mutagenesis of a potential G box recognition sequence for Egr-1 did not impair the Egr-1 responsiveness of the insulin promoter, suggesting that regulation of insulin gene expression by Egr-1 is probably mediated through additional transcription factors. Overexpression of Egr-1 increased, and reduction of Egr-1 expression decreased, transcriptional activation of the glucose-responsive FarFlat minienhancer within the rat insulin I promoter despite the absence of demonstrable Egr-1-binding activity to FarFlat sequences. Notably, augmenting Egr-1 expression levels in insulin-producing cells increased the mRNA and protein expression levels of pancreas duodenum homeobox-1 (PDX-1), a major transcriptional regulator of glucose-responsive activation of the insulin gene. Increasing Egr-1 expression levels enhanced PDX-1 binding to insulin promoter sequences, whereas mutagenesis of PDX-1-binding sites reduced the capacity of Egr-1 to activate the insulin promoter. We propose that changes in Egr-1 expression levels in response to extracellular signals, including glucose, can regulate PDX-1 expression and insulin production in pancreatic β-cells.
8
Yan, Shi-Fang, Jiesheng Lu, Linna Xu, Yu Shan Zou, Joern Tongers, Walter Kisiel, Nigel Mackman, David J. Pinsky, and David M. Stern. "Pulmonary expression of early growth response-1: biphasic time course and effect of oxygen concentration." Journal of Applied Physiology 88, no. 6 (June 1, 2000): 2303–9. http://dx.doi.org/10.1152/jappl.2000.88.6.2303.
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Hypoxia induces complex adaptive responses. In this report, induction of early growth response-1 (Egr-1) transcripts in lungs of mice subjected to hypoxia is shown to be dose and time dependent. Within 30 min of hypoxia, Egr-1 transcripts were ∼20-fold elevated in 6% oxygen, ∼5.2-fold increased by 10% oxygen, and returned to the normoxic baseline by 12% oxygen. Time course studies up to 48 h showed a biphasic profile with an initial steep rise in Egr-1 transcripts after 0.5 h of hypoxia and a second elevation beginning after 20–24 h. Hypoxic induction of Egr-1 was paralleled by enhanced expression of the downstream target gene tissue factor. Egr-1 and tissue factor antigen were visualized in bronchial and vascular smooth muscle and in alveolar macrophages. Egr-1 has the capacity to modulate expression of genes involved in the remodeling of the extracellular matrix and properties of smooth muscle, thus possibly contributing to the pulmonary response to chronic hypoxia.
9
Hjoberg, Josephine, Louis Le, Amy Imrich, Venkat Subramaniam, Sheeba I. Mathew, Joseph Vallone, Kathleen J. Haley, Francis H. Y. Green, Stephanie A. Shore, and Eric S. Silverman. "Induction of early growth-response factor 1 by platelet-derived growth factor in human airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 286, no. 4 (April 2004): L817—L825. http://dx.doi.org/10.1152/ajplung.00190.2003.
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Platelet-derived growth factors (PDGF) may contribute to the activation and growth of smooth muscle that is characteristic of airway remodeling in asthmatic patients. Early growth response 1 (EGR-1) is a transcription factor that is induced in several cell types by PDGF and may mediate some of the effects of PDGF. We show that human airway smooth muscle cells in cell culture express EGR-1 ∼1 h after addition of PDGF. Analysis of the EGR-1 promoter indicates that a serum response element located between 663 and 654 bp 5′ to the ATG start site is essential for this induction. Serum response factor, E26 transcription factor-like protein 1, and serum protein 1 bind to this region. PDGF causes phosphorylation of ERK1/2 and is temporally associated with E26 transcription factor-like protein 1 phosphorylation. Finally, the specific ERK1/2 inhibitor U-0126 abolishes PDGF-induced expression of EGR-1 in these cells. On the basis of these data, we speculated that EGR-1 would be increased in airway smooth muscle of asthmatic patients compared with nonasthmatic controls. Using immunohistochemistry, we found that EGR-1 protein was expressed in airway smooth muscle cells and epithelial cells of asthmatic patients and nonasthmatic controls; however, there was no significant difference in the intensity of staining between groups. EGR-1 was similarly expressed in the lungs of mice with and without ovalbumin-induced airway inflammation; however, there was no difference between groups by immunohistochemistry and quantitative PCR. Although EGR-1 is induced by PDGF in human airway smooth muscle cells in cell culture, the role of EGR-1 in airway remodeling and asthma remains to be established.
10
Chang, Yao, Heng-Huan Lee, Yu-Te Chen, Jean Lu, Shih-Yi Wu, Chaio-Wei Chen, Kenzo Takada, and Ching-Hwa Tsai. "Induction of the Early Growth Response 1 Gene by Epstein-Barr Virus Lytic Transactivator Zta." Journal of Virology 80, no. 15 (August 1, 2006): 7748–55. http://dx.doi.org/10.1128/jvi.02608-05.
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ABSTRACT Early growth response 1 (Egr-1) is a cellular transcription factor involved in diverse biologic functions. Egr-1 has been associated with Epstein-Barr virus (EBV) infection, but it is still unknown whether any EBV protein regulates Egr-1 expression. In this study, we first showed that EBV reactivation is involved in upregulation of Egr-1 and that Egr-1 can be induced by Zta, an EBV lytic transactivator. Zta not only binds to the Egr-1 promoter but also activates the ERK signaling pathway to trigger binding of Elk-1 to the Egr-1 promoter. In addition, knockdown of Egr-1 significantly reduces the spontaneous expression of Zta and Rta in EBV-infected 293 cells, suggesting that a positive-feedback network involving Egr-1 is required for EBV reactivation. This study also implies that Zta has the potential to affect expression of certain genes through Egr-1.
11
Shao, Hui, Dwight H. Kono, Ling-Yu Chen, Elyssa M. Rubin, and Jonathan Kaye. "Induction of the Early Growth Response (Egr) Family of Transcription Factors during Thymic Selection." Journal of Experimental Medicine 185, no. 4 (February 17, 1997): 731–44. http://dx.doi.org/10.1084/jem.185.4.731.
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There is little known about the regulation of gene expression during TCR-mediated differentiation of immature CD4+8+ (double positive) thymocytes into mature T cells. Using the DPK CD4+8+thymocyte precursor cell line, we demonstrate that the early growth response-1 gene (Erg-1), encoding a zinc finger transcription factor, is rapidly upregulated after TCR stimulation. We also report that Egr-1 is expressed by a subset of normal double positive thymocytes in the thymic cortex, as well by a majority of medullary single positive thymocytes. Expression of Egr-1 is dramatically reduced in the thymus of major histocompatibility complex knockout mice, but can be induced by anti-CD3 antibody stimulation of isolated thymocytes from these animals. These and other data suggest that high level expression of Egr-1 in the thymus is a consequence of selection. A similar pattern of expression is found for family members Egr-2 and Egr-3. Using the DPK cell line, we also demonstrate that expression of Egr-1, 2, and 3 is dependent upon ras activation, as is the initiation of differentiation to a single positive cell. In contrast, the calcineurin inhibitor cyclosporin A, which inhibits DPK cell differentiation as well as positive selection, inhibits expression of Egr-2 and Egr-3, but not Egr-1. The identification of the Egr family in this context represents the first report of a link between the two known signaling pathways involved in positive selection and downstream transcriptional regulators.
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Miyazaki, Toru, and François A. Lemonnier. "Modulation of Thymic Selection by Expression of an Immediate-early Gene, Early Growth Response 1 (Egr-1)." Journal of Experimental Medicine 188, no. 4 (August 17, 1998): 715–23. http://dx.doi.org/10.1084/jem.188.4.715.
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The potential involvement of early growth response (Egr)-1, a zinc-finger transcription factor belonging to the immediate-early genes, in positive/negative selection of thymocytes has been implicated by its expression in the population of CD4+CD8+ double positive (DP) cells undergoing selection. To further investigate this possibility, transgenic mice overexpressing Egr-1 in thymocytes were bred with a transgenic mouse line expressing a T cell receptor (TCR) recognizing the H-Y male antigen in the context of H-2b class I major histocompatibility complex (MHC) molecules. In Egr-1/TCR H-Y double-transgenic mice, efficient positive selection of H-Y CD8+ T cells occurred, even in mice on either a nonselecting H-2d background or a β2-microglobulin (β2m)-deficient background in which the expression of class I MHC heavy chains is extremely low; no positive selection was observed on a Kb−/−Db−/−β2m−/− background where class I MHC expression is entirely absent. Similarly, when the Egr-1 transgene was introduced into a class II MHC–restricted TCR transgenic mouse line, Egr-1/TCR double-transgenic mice revealed increased numbers of CD4+ T cells selected by class II MHC, as well as significant numbers of CD8+ T cells selected by class I MHC (for which the transgenic TCR might have weak affinity). Thus, Egr-1 overexpression allows positive selection of thymocytes via TCR–MHC interactions of unusually low avidity, possibly by lowering the threshold of avidity required for positive selection. Supporting this possibility, increased numbers of alloreactive T cells were positively selected in Egr-1 transgenic mice, resulting in a strikingly enhanced response against allo-MHC. These results suggest that expression of Egr-1 and/or its target gene(s) may directly influence the thresholds required for thymocyte selection.
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Jalagadugula, Gauthami, Dhanasekaran N. Danny, Kim Soochong, Satya P. Kunapuli, and A. Koneti Rao. "Early Growth Response Factor EGR-1 Regulates Gαq Gene in Megakaryocytic Cells." Blood 108, no. 11 (November 16, 2006): 1518. http://dx.doi.org/10.1182/blood.v108.11.1518.1518.
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Abstract Gαq (Gene GNAQ) plays a major role in platelet signal transduction but little is known regarding its transcriptional regulation. We studied Gαq promoter activity using luciferase reporter gene assays in human erythroleukemia (HEL) cells treated with 10 nM of phorbol 12-myristate 13-acetate (PMA) for 24 h to induce megakaryocytic (MK) transformation. RT-PCR analysis of HEL cell RNA revealed that Gαq mRNA was relatively low in untreated cells and it increased after PMA treatment with a peak at 5 h. Immunoblot analysis of HEL lysates showed enhanced Gαq expression with PMA. Luciferase reporter gene studies on full length construct (upto −1116 bp from ATG) and its serial 5′ truncations revealed a negative regulatory site at −238/−202 and two positive sites at −203/−138 and −1116/−731. In the region −238/−202 consensus sites were noted for two transcription factors PU.1 and GATA-1 that are known to regulate several megakaryocytic genes. Deletions of these sites alone or together revealed no change in the transcriptional activity of the gene in reporter studies. The positive region −203/−138 contained two overlapping Sp1/AP-2/EGR-1 consensus sites at −202/−189 and −164/−150. Gel shift studies were performed on oligonucleotides 1 (−203/−175) and 2 (−174/−152) using HEL cell extracts. Protein binding occured with Gαq oligonucleotides 1 and 2, which was competed with excess unlabeled oligos but not by unlabeled Sp1 or AP-2 consensus oligos. Supershift assay using antibody against Sp1 revealed neither competition nor supershift, suggesting that Sp1 does not bind to these oligonucleotides. No protein binding was noted when Gαq oligos 1 or 2 were incubated with extracts known to contain Sp1 or AP-2. These results indicate that Sp1 and AP-2 do not bind to the Gαq oligonucleotide regions. Protein binding to oligonucleotides 1 and 2 was abolished by excess unlabeled consensus EGR-1 oligo, and by immunodepletion of the EGR-1 protein from the nuclear extract with anti-EGR-1 antibody. These experiments reveal that EGR-1 binds to both Gαq oligonucleotides −203/−175 and −174/−152. In luciferase reporter studies mutations in EGR-1 sites present in both oligonucleotides 1 and 2 markedly decreased gene activity indicating functional relevance. In further studies, reduction in endogenous EGR-1 expression with antisense oligonucleotide to EGR-1 inhibited PMA induced Gαq transcription and protein in HEL cells. Lastly, EGR-1 deficient mouse platelets also showed ~50% reduction in the Gαq protein (immunoblotting) relative to wild type platelets. These studies suggest that Gαq gene is regulated during PMA induced differentiation by EGR-1, a transcription factor that regulates a wide array of genes involved in cellular proliferation, differentiation, and apoptosis, and in vascular response to injury and atherosclerosis.
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Jeong, Kyuho, Jihyun Je, Theodomir Dusabimana, Hwajin Kim, and Sang Won Park. "Early Growth Response 1 Contributes to Renal IR Injury by Inducing Proximal Tubular Cell Apoptosis." International Journal of Molecular Sciences 24, no. 18 (September 19, 2023): 14295. http://dx.doi.org/10.3390/ijms241814295.
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Renal ischemia–reperfusion (IR) causes acute kidney injury due to oxidative stress, tubular inflammation, and apoptosis. Early growth response 1 (Egr-1) is a transcription factor belonging to the immediate early gene family and is known to regulate cell proliferation, differentiation, and survival. Egr-1 expression is induced during renal IR; however, its pathogenic role and underlying mechanisms remain elusive. Here, we investigated the function of Egr-1 during renal IR using C57BL/6 mice and cultured renal proximal tubular HK-2 cells. Egr-1 expression increased immediately, 1–4 h after IR, whereas plasma creatinine and oxidative stress increased progressively over 24 h after IR. Egr-1 overexpression showed greater increases in plasma creatinine, renal tubular injury, and apoptosis than in the control after IR. Egr-1 overexpression also showed significant neutrophil infiltration and increased pro-inflammatory cytokines (TNF-α, MIP-2, and IL-6) after IR. Consistently, proximal tubular HK-2 cells showed immediate induction of Egr-1 at 1 h after hypoxia and reoxygenation, where its downstream target, p53, was also increased. Interestingly, Egr-1 overexpression enhanced p53 levels and tubular apoptosis, while the knockdown of Egr-1 reduced p53 levels and tubular apoptosis after H2O2 treatment. Egr-1 was recruited to the p53 promoter, which activates p53 transcription, and Egr-1 induction occurred through Erk/JNK signaling kinases, as the specific inhibitors blocked its expression. Taken together, these results show that Egr-1 is upregulated in proximal tubular cells and contributes to renal IR injury by inducing tubular apoptosis, mediated by p53 transcriptional activation. Thus, Egr-1 could be a potential therapeutic target for renal IR injury.
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Pritchard, Michele T., Sanjoy Roychowdhury, Megan R. McMullen, Luping Guo, Gavin E. Arteel, and Laura E. Nagy. "Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 6 (December 2007): G1124—G1133. http://dx.doi.org/10.1152/ajpgi.00325.2007.
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Early growth response (Egr)-1 is a transcription factor that regulates genes involved in inflammation, innate and adaptive immunity, coagulation, and wound healing; however, little is known about the role of Egr-1 in acute liver injury. We tested the hypothesis that Egr-1 is involved in acute liver injury induced by galactosamine/lipopolysaccharide (GalN/LPS). GalN/LPS exposure biphasically increased hepatic egr-1 mRNA accumulation at 1 h and again at 4–5.5 h after treatment in wild-type mice. Within 4–5.5 h after GalN/LPS exposure, wild-type mice exhibited histological evidence of hepatocyte injury, cell death, and extensive areas of hemorrhage, as well as increased plasma alanine aminotransferase activities. In contrast, these parameters were largely attenuated in egr-1−/−mice. The initial expression of tumor necrosis factor-α, macrophage inflammatory protein-2, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 mRNA or protein was equivalent between genotypes at 1 h after GalN/LPS administration. However, at subsequent time points, hepatic expression of these genes was decreased in egr-1−/−compared with wild-type mice. In addition, neutrophil extravasation from hepatic sinusoids into the liver parenchyma was decreased in egr-1−/−compared with wild-type mice 4 h after GalN/LPS. Whereas caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei were detected in wild-type mice at 4 and 5.5 h after GalN/LPS administration, respectively, these markers of apoptosis were delayed in egr-1−/−mice. Delayed development of apoptosis was associated with an extension of survival by 1 h in egr-1−/−compared with wild-type mice. These data demonstrate that Egr-1 plays an important role in acceleration of hepatic inflammation, apoptosis, and subsequent mortality in GalN/LPS-induced acute liver injury.
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PIGNATELLI, Miguel, Rosario LUNA-MEDINA, Arturo PÉREZ-RENDÓN, Angel SANTOS, and Ana PEREZ-CASTILLO. "The transcription factor early growth response factor-1 (EGR-1) promotes apoptosis of neuroblastoma cells." Biochemical Journal 373, no. 3 (August 1, 2003): 739–46. http://dx.doi.org/10.1042/bj20021918.
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Early growth response factor-1 (EGR-1) is an immediate early gene, which is rapidly activated in quiescent cells by mitogens or in postmitotic neurons after depolarization. EGR-1 has been involved in diverse biological functions such as cell growth, differentiation and apoptosis. Here we report that enforced expression of the EGR-1 gene induces apoptosis, as determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end labelling (TUNEL) analysis, in murine Neuro2A cells. In accordance with this role of EGR-1 in cell death, antisense oligonucleotides increase cell viability in cells cultured in the absence of serum. This apoptotic activity of the EGR-1 appears to be mediated by p73, a member of the p53 family of proteins, since an increase in the amount of p73 is observed in clones stably expressing the EGR-1 protein. We also observed an increase in the transcriptional activity of the mdm2 promoter in cells overexpressing EGR-1, which is paralleled by a marked decrease in the levels of p53 protein, therefore excluding a role of this protein in mediating EGR-1-induced apoptosis. Our results suggest that EGR-1 is an important factor involved in neuronal apoptosis.
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Tseng, Yen-Chiang, Chih-Wen Shu, Hui-Min Chang, Yi-Hsuan Lin, Yen-Han Tseng, Han-Shui Hsu, Yih-Gang Goan, and Ching-Jiunn Tseng. "Assessment of Early Growth Response 1 in Tumor Suppression of Esophageal Squamous Cell Carcinoma." Journal of Clinical Medicine 11, no. 19 (September 29, 2022): 5792. http://dx.doi.org/10.3390/jcm11195792.
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Background: Esophageal squamous cell carcinoma (ESCC) is associated with poor survival despite surgical resection, and its pathogenesis has been broadly investigated in the past decade. Early growth response 1 (EGR-1) could involve regulating tumor development in ESCC cells. Methods: An attempt was made to examine the molecular and cellular influence of EGR-1 in esophageal cancer cells by RNA extraction, real-time PCR (qRT-PCR), cell culture, small interfering RNA (siRNA) knockdown, western blot, migration assay, and cell viability assay. One hundred and forty-four samples of ESCC were collected from our hospital and analyzed. Significantly higher EGR-1 expression was noted in tumor-adjacent normal tissue compared with tumor lesions. Results: The univariate analysis showed no significant impacts of EGR-1 expression on patients’ survival. However, after adjusting for the pathological stage, patients with EGR-1 expression > 68th percentile had lower risks of cancer-related death. Moreover, knockdown of EGR-1 significantly enhanced cell migration, invasion, and resistance to chemotherapeutic agents in two ESCC cell lines. Conclusions: EGR-1 plays a key role in tumor suppression involving tumor viability suppression and reflects the treatment effect of current chemotherapy for ESCC.
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Lee, Chun Geun, Soo Jung Cho, Min Jong Kang, Svetlana P. Chapoval, Patty J. Lee, Paul W. Noble, Teshome Yehualaeshet, et al. "Early Growth Response Gene 1–mediated Apoptosis Is Essential for Transforming Growth Factor β1–induced Pulmonary Fibrosis." Journal of Experimental Medicine 200, no. 3 (August 2, 2004): 377–89. http://dx.doi.org/10.1084/jem.20040104.
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Fibrosis and apoptosis are juxtaposed in pulmonary disorders such as asthma and the interstitial diseases, and transforming growth factor (TGF)-β1 has been implicated in the pathogenesis of these responses. However, the in vivo effector functions of TGF-β1 in the lung and its roles in the pathogenesis of these responses are not completely understood. In addition, the relationships between apoptosis and other TGF-β1–induced responses have not been defined. To address these issues, we targeted bioactive TGF-β1 to the murine lung using a novel externally regulatable, triple transgenic system. TGF-β1 produced a transient wave of epithelial apoptosis that was followed by mononuclear-rich inflammation, tissue fibrosis, myofibroblast and myocyte hyperplasia, and septal rupture with honeycombing. Studies of these mice highlighted the reversibility of this fibrotic response. They also demonstrated that a null mutation of early growth response gene (Egr)-1 or caspase inhibition blocked TGF-β1–induced apoptosis. Interestingly, both interventions markedly ameliorated TGF-β1–induced fibrosis and alveolar remodeling. These studies illustrate the complex effects of TGF-β1 in vivo and define the critical role of Egr-1 in the TGF-β1 phenotype. They also demonstrate that Egr-1–mediated apoptosis is a prerequisite for TGF-β1–induced fibrosis and remodeling.
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NOSE, Kiyoshi, and Motoi OHBA. "Functional activation of the egr-1 (early growth response-1) gene by hydrogen peroxide." Biochemical Journal 316, no. 2 (June 1, 1996): 381–83. http://dx.doi.org/10.1042/bj3160381.
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The redox-based regulation of gene expression is one of the fundamental mechanisms of cellular functions, and hydrogen peroxide seems to act as an intracellular second messenger of signal transduction of cytokines. Hydrogen peroxide at non-toxic doses induced the accumulation of mRNA for the early growth response-1 (egr-1) gene in mouse osteoblastic cells. The Egr-1 protein is a transcription factor that binds the GCGGGGGCG sequence and contains a zinc-finger structure that is essential for DNA binding. Egr-1 protein is sensitive to oxidative stress and loses specific DNA-binding activity when exposed to high levels of oxidative stress. Incubating cells with hydrogen peroxide at about 50 μM, however, increased the accumulation of Egr-1 protein, and the Egr-1 product seemed to be functional, judging by its binding activity to the GCGGGGGCG sequence and its ability to activate the chloramphenicol acetyltransferase reporter gene under the control of the human thymidine kinase enhancer containing the Egr-1 binding sequence. It was reported that the activity of Egr-1 protein as a transcription factor was negatively regulated by active oxygens. However, with appropriate concentrations of active oxygen, its capacity to bind a specific DNA sequence and to enhance the transcriptional activity of target genes is thought to be elevated.
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Khomenko, Tetyana, Sandor Szabo, Xiaoming Deng, Martin R. Jadus, Hideki Ishikawa, Klara Osapay, Zsuzsa Sandor, and Longchuan Chen. "Suppression of early growth response factor-1 with egr-1 antisense oligodeoxynucleotide aggravates experimental duodenal ulcers." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 6 (June 2006): G1211—G1218. http://dx.doi.org/10.1152/ajpgi.00078.2005.
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Previously, we demonstrated that cysteamine releases endothelin-1 in the rat duodenal mucosa, followed by increased expression of early growth response factor-1 (egr-1). We hypothesized that egr-1 is a key mediator gene in the multifactorial mechanisms of duodenal ulcer development and healing because its protein, transcription factor product Egr-1, regulates the expression of angiogenic growth factors. We wanted to determine the effect of egr-1 antisense oligonucleotide on cysteamine-induced duodenal ulcers as well as on the expression of bFGF, PDGF, and VEGF, of which synthesis is modulated by Egr-1. An antisense oligonucleotide to egr-1 was used to inhibit the synthesis of Egr-1 and to determine its effect on ulcer formation in the rat model of cysteamine-induced duodenal ulceration. Real-time RT-PCR and Western blot analysis were used to assess the expression of Egr-1 mRNA and protein as well as ERK, bFGF, PDGF, and VEGF. The antisense Egr-1 oligonucleotide inhibited the expression of egr-1 mRNA and protein and increased the duodenal ulcer size from 8.1 ± 1.8 mm2 in controls to 20.7 ± 4.0 mm2 ( P < 0.01). Cysteamine induced phosphorylation of ERK1/2 and enhanced the synthesis of bFGF, PDGF, and VEGF in the preulcerogenic stages of duodenal ulceration, whereas egr-1 antisense oligonucleotide markedly decreased the expression of these growth factors in the duodenal mucosa. We also demonstrated that Egr-1 expression relates to the ulcerogenic effect of cysteamine because these actions were not exerted by the toxic analog ethanolamine. Thus Egr-1 seems to play a critical role in duodenal ulceration because Egr-1 downregulation aggravates experimental duodenal ulcers, most likely through the transcriptional inhibition of bFGF, PDGF, and VEGF synthesis.
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Rupprecht, H. D., V. P. Sukhatme, J. Lacy, R. B. Sterzel, and D. L. Coleman. "PDGF-induced Egr-1 expression in rat mesangial cells is mediated through upstream serum response elements." American Journal of Physiology-Renal Physiology 265, no. 3 (September 1, 1993): F351—F360. http://dx.doi.org/10.1152/ajprenal.1993.265.3.f351.
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Platelet-derived growth factor (PDGF) has been implicated in the process of mesangial cell (MC) proliferation in vitro and in vivo. To investigate early changes in gene expression that couple biochemical events with changes in phenotype in PDGF-stimulated cultured MC, we studied expression of the early growth response gene 1 (Egr-1), a member of the family of immediate early genes. Our findings show that protein tyrosine phosphorylation is required for induction of Egr-1 mRNA and proliferation by PDGF in MC. Nuclear run-off assays show that Egr-1 induction occurs at the transcriptional level. An 11.3-fold increase in Egr-1 transcription rate was observed as early as 5 min after PDGF stimulation of MC. Promoter deletion analysis revealed that the region critical for Egr-1 inducibility by PDGF contains serum response element (SRE) consensus sequences. Sequential deletion of the Egr-1 SREs led to a stepwise drop in promoter activity, suggesting that PDGF induces Egr-1 transcription through SREs in the Egr-1 promoter region. Interestingly, electrophoretic mobility shift assays, with an Egr-1 SRE as probe, demonstrate that protein-SRE complexes of differing size undergo modest quantitative changes following PDGF stimulation. These data in MC suggest that the upstream SREs mediate the transcriptional induction of Egr-1 by PDGF.
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Tamm, Ingo, Karin Schmelz, Bernd Dörken, and Mandy Wagner. "Survivin Is Negatively Regulated by Early Growth Response (Egr)-1 Transcription Factor in Acute Myeloid Leukemia." Blood 108, no. 11 (November 16, 2006): 1943. http://dx.doi.org/10.1182/blood.v108.11.1943.1943.
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Abstract Survivin, a member of the inhibitor of apoptosis protein family, is involved in both, inhibition of apoptosis and regulation of cell division. It is expressed in embryonic and fetal tissues as well as in the majority of human leukemias, but is undetectable in normal differentiated adult tissue in vivo. The molecular mechanisms involved in the cancer-specific re-expression of survivin are unclear. In this study, we describe a novel mechanism for over-expression of survivin in AML. Using electrophoretic mobility shift assays (EMSA), we show that the early growth response (Egr)-1 transcription factor binds to the sequence 5′ GAGGGGGCG 3′ within the human survivin promoter after induction by phorbol 12-myristate-13-acetate (PMA) in vitro. Furthermore, chromatin immunoprecipitation (ChIP) analysis confirmed the specific binding of Egr-1 to the proximal survivin promoter in PMA treated entire leukemia cells. To further analyze the functionality of the Egr-1 site within the survivin promoter in entire cells, transient transfections of p53 wildtype and mutated cell lines with wildtype Egr-1 expression vector were performed. In these overexpression experiments, mRNA and protein levels of survivin but not of control protein were downregulated after exogenous expression of wildtype Egr-1. Using reporter-gene assays, basal survivin promoter activity was decreased significantly by wildtype Egr-1 transfection, whereas mutant Egr-1 did not change activity of the survivin promoter, implying that Egr-1 specifically blocks survivin expression at the transcriptional level. In addition, Egr-1 over-expression sensitized cells to TRAIL-induced apoptosis. To investigate the expression pattern of Egr-1 in different AML cell lines and control samples from healthy donors, we analyzed the expression of Egr-1 by RT-PCR. Fitting with the above shown data, Egr-1 was expressed at significantly lower levels in AML cell lines expressing high survivin levels than in healthy control samples with low survivin levels. Taken together, we show that the transcription factor Egr-1 binds to the human survivin promoter in vitro and in entire cells, downregulates survivin expression independently of p53 and sensitizes cells to TRAIL-induced apoptosis. Since Survivin is often overexpressed in AML, downregulating Survivin expression by activating Egr-1 may be an interesting therapeutic option.
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Ito, E., N. Nomura, and R. Narayanan. "Transcriptional regulation of early growth response genes in FOS-expressing PC-12 cells." Cell Regulation 1, no. 4 (March 1990): 347–57. http://dx.doi.org/10.1091/mbc.1.4.347.
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Deregulated c-fos expression in the rat pheochromocytoma cell line, PC-12, causes pronounced downregulation of nerve growth factor (NGF)-induced c-fos and c-jun activation, accompanied by a block in NGF-induced differentiation of PC-12 cells. The FOS-expressing PC-12 cells were exposed to diverse agents such as NGF, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), dibutyryl cyclic adenosine 3',5' monophosphate (db cAMP), and Ca-ionophore; and the expression of egr-1, c-fos, c-jun, jun-B, and jun-D was analyzed. Pronounced downregulation of c-fos, c-jun, and--to a lesser extent--jun-B was observed on treatment with NGF, bFGF, db cAMP, and Ca-ionophore, whereas EGF-induced activation of these early response genes was not inhibited in FOS-expressing PC-12 cells. Ca-ionophore- and db cAMP-induced egr-1 activation in PC-12 fos cells was completely inhibited. Both parent and PC-12 fos cells expressed similar high basal levels of jun-D, whose expression was the least regulatable by all of these agents. Transfection of fos promoter-chloramphenicol acetyltransferase (promoter-CAT) plasmid into these stable FOS-expressing PC-12 cells revealed that these effects are exerted at the fos promoter level.
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Li, Suling, Alistair L. J. Symonds, Bo Zhu, Mengya Liu, Meera V. Raymond, Tizong Miao, and Ping Wang. "Early Growth Response Gene-2 regulates the development of B and T cells (153.15)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 153.15. http://dx.doi.org/10.4049/jimmunol.186.supp.153.15.
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Abstract Understanding of how transcription factors are involved in lymphocyte development still remains a challenge. It has been showed that Egr-2 deficiency results in impaired NKT cell development and defective positive selection of T cells. Here we investigated the development of T, B and NKT cells in Egr-2 transgenic mice and the roles in the regulation of distinct stages of B and T cell development. The expression of Egr1, 2 and 3 were analysed at different stages of T and B cell development by RT-PCT and results showed that the expression was strictly regulated at different stages. Forced expression of Egr-2 in CD2+ lymphocytes resulted in a severe reduction of CD4+CD8+ (DP) cells in thymus and pro-B cells in bone marrow, which was associated with reduced expression of Notch1 in ISP thymocytes and Pax5 in pro-B cells, suggesting that retraction of Egr-2 at the ISP and pro-B cell stages is important for the activation of lineage differentiation programs. In contrast to reduction of DP and pro-B cells, Egr-2 enhanced the maturation of DP cells into single positive (SP) T and NKT cells in thymus, and immature B cells into mature B cells in bone marrow. Our results demonstrate that Egr-2 expressed in restricted stages of lymphocyte development plays a dynamic, but similar role for the development of T, NKT and B cells
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Sukhatme, V. P. "Early transcriptional events in cell growth: the Egr family." Journal of the American Society of Nephrology 1, no. 6 (December 1990): 859–66. http://dx.doi.org/10.1681/asn.v16859.
Full textAbstract:
How eucaryotic cells respond to growth signals is a topic of considerable interest. Though much attention has focused on second messenger pathways, in recent years, progress has been made on elucidating the transcriptional events that lie more distally in the signal transduction process. Indeed, mitogens regulate the induction of several genes without the need for de novo protein synthesis. A subset of these so-called cellular immediate-early genes encode transcription factors. This review focuses on the early growth response group of zinc finger transcriptional factors. These genes are also induced by diverse agents in contexts outside of cell growth. Thus, their characterization should provide important insights into how cellular responses to diverse extracellular signals are mediated.
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Wang, Ping, Tizong Miao, Alistair Symonds, and Suling Li. "Early growth response genes -2 and -3 are required for naïve T cell activation and primary response against virus infection (P1150)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 64.22. http://dx.doi.org/10.4049/jimmunol.190.supp.64.22.
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Abstract T cells robustly respond to virus infection. Egr-2 and -3 are induced in both naïve and tolerant T cells (PMC2652694, PMID15585857, PMID15834410). The deficiency of Egr-2 and -3 specifically in B and T cells results in autoimmunity (PMID23021953). It is however unknown whether they also play roles in protective immmunoresponses. We have now shown that Egr-2 and -3 are required for naïve T cell activation in response to virus infection. Defect in Egr-2 and -3 restrains the IL-2 production and the expansion of viral specific CD4 and CD8 T cells, leading to the development of chronic infection despite active phenotypes and excessive production of IFNg. The induced Egr-2 and -3 in naïve T cells are essential for the maintenance of optimal AP-1 activation and IL-2 production leading to the rapid expansion of viral specific T cells. In addition to the proliferation of viral specific T cells, Egr-2 and -3 control the production of inflammatory cytokines and the activation phenotypes of viral specific T cells at early stages of infection to limit inflammatory pathology and build a pool of responding T cells for a robust anti-viral effect with minimum immunopathology. The functions of Egr-2 and -3 are limited in naïve T cells in primary immunoresponses and are not involved in the development of the memory pool and secondary responses. In conclusion, in addition to the maintenance of immunohomeostasis, Egr-2 and -3 are important to primary immune responses against virus infection.
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Ziegelhoeffer, Tibor, Matthias Heil, Silvia Fischer, Borja Fernández, Wolfgang Schaper, Klaus T. Preissner, Elisabeth Deindl, and Judith-Irina Pagel. "Role of early growth response 1 in arteriogenesis: Impact on vascular cell proliferation and leukocyte recruitment in vivo." Thrombosis and Haemostasis 107, no. 03 (2012): 562–74. http://dx.doi.org/10.1160/th11-07-0490.
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SummaryBased on previous findings that early growth response 1 (Egr-1) participates in leukocyte recruitment and cell proliferation in vitro, this study was designed to investigate its mode of action during arteriogenesis in vivo. In a model of peripheral arteriogenesis, Egr-1 was significantly upregulated in growing collaterals of wild-type (WT) mice, both on mRNA and protein level. Egr-1−/− mice demonstrated delayed arteriogenesis after femoral artery ligation. They further showed increased levels of monocytes and granulocytes in the circulation, but reduced levels in adductor muscles under baseline conditions. After femoral artery ligation, elevated numbers of macrophages were detected in the perivascular zone of collaterals in Egr-1−/− mice and mRNA of leukocyte recruitment mediators was upregulated. Other Egr family members (Egr-2 to -4) were significantly upregulated only in Egr-1−/− mice, suggesting a mechanism of counterbalancing Egr-1 deficiency. Moreover, splicing factor-1, downregulated in WT mice after femoral artery ligation in the process of increased vascular cell proliferation, was upregulated in Egr-1−/− mice. αSM-actin on the other hand, significantly downregulated in WT mice, showed no differential expression in Egr-1−/− mice. While cell cycle regulator cyclin E and cdc20 were upregulated in Egr-1−/− mice, cyclin D1 expression decreased below the detection limit in collaterals, and the proliferation marker ki67 was not differentially expressed. In conclusion, compensation for deficiency in Egr-1 function in leukocyte recruitment can presumably be mediated by other transcription factors; however, Egr-1 is indispensable for effective vascular cell cycle progression in arteriogenesis.
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Han, Peng, Hilda Guerrero-Netro, Anthony Estienne, Binyun Cao, and Christopher A. Price. "Regulation and action of early growth response 1 in bovine granulosa cells." Reproduction 154, no. 4 (October 2017): 547–57. http://dx.doi.org/10.1530/rep-17-0243.
Full textAbstract:
Fibroblast growth factors (FGF) modify cell proliferation and differentiation through receptor tyrosine kinases, which stimulate the expression of transcription factors including members of the early growth response (EGR) family. In ovarian granulosa cells, most FGFs activate typical response genes, although the role of EGR proteins has not been described. In the present study, we determined the regulation of EGR mRNA by FGFs and explored the role of EGR1 in the regulation of FGF-response genes. Addition of FGF1, FGF2, FGF4 or FGF8b increased EGR1 and EGR3 mRNA levels, whereas FGF18 increased only EGR1 mRNA abundance. No mRNA encoding EGR2 or EGR4 was detected. Overexpression of EGR1 increased EGR3 mRNA levels as well as the FGF-response genes SPRY2, NR4A1 and FOSL1 and also increased the phosphorylation of MAPK3/1. Knockdown of EGR3 did not alter the ability of FGF8b to stimulate SPRY2 mRNA levels. These data demonstrate the regulation of EGR1 and EGR3 mRNA abundance by FGFs in granulosa cells and suggest that EGR1 is likely an upstream component of FGF signaling in granulosa cells.
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Kenzel, Sybille, Sandra Santos-Sierra, Sachin D. Deshmukh, Inga Moeller, Bilge Ergin, Katherine A. Fitzgerald, Egil Lien, Shizuo Akira, Douglas T. Golenbock, and Philipp Henneke. "Role of p38 and Early Growth Response Factor 1 in the Macrophage Response to Group B Streptococcus." Infection and Immunity 77, no. 6 (March 30, 2009): 2474–81. http://dx.doi.org/10.1128/iai.01343-08.
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ABSTRACT Group B streptococcus (GBS), the most frequent single isolate in neonatal sepsis and meningitis, potently activates inflammatory macrophage genes via myeloid differentiation antigen 88 (MyD88). However, events parallel to and downstream of MyD88 that instruct the macrophage response are incompletely understood. In this study, we found that only MyD88, not the Toll-like receptor (TLR) adapter proteins MAL/TIRAP, TRIF, and TRAM, essentially mediates the cytokine (tumor necrosis factor [TNF] and interleukin-6) and chemokine (RANTES) responses to whole GBS organisms, although MAL, TRIF, and TRAM have been shown to mediate the responses to substructures in other gram-positive and gram-negative bacteria. GBS-induced, MyD88-dependent phosphorylation of the mitogen-activated protein kinase p38 activated the transcription factor AP-1 and early growth response factor 1 (Egr-1) but not NF-κB. Furthermore, phosphorylation of Ets-like molecule 1 (Elk-1) was mediated by p38. However, in contrast to Egr-1 and AP-1, Elk-1 was dispensable for transcriptional activation of TNF by GBS organisms. Studies of macrophages from Elk-1-deficient mice revealed that Elk-1 was furthermore nonessential for the TNF responses to purified TLR2 and TLR4 agonists, which was in notable contrast to what was revealed in studies employing in vitro expression systems. In conclusion, MyD88, p38, and Egr-1, but not Elk-1, essentially mediate the inflammatory cytokine response to GBS organisms.
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Schabbauer, Gernot, Bernhard Schweighofer, Diana Mechtcheriakova, Markus Lucerna, Bernd Binder, and Erhard Hofer. "Nuclear factor of activated T cells and early growth response-1 cooperate to mediate tissue factor gene induction by vascular endothelial growth factor in endothelial cells." Thrombosis and Haemostasis 97, no. 06 (2007): 979–87. http://dx.doi.org/10.1160/th07-01-0037.
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SummaryBased on the finding that tissue factor belongs to a group of genes upregulated in endothelial cells by VEGF, but not by EGF, we investigated signals selectively triggered by VEGF. Whereas the transcription factor early growth response (EGR)-1, which has previously been shown by us to be essentially involved in tissue factor gene regulation, was similarly induced by both factors, one major difference between VEGF and EGF signaling was the activation of the Ca++-mediated calcineurin/nuclear factor of activated T cells (NFAT) pathway by VEGF. Consistent with the importance of this pathway for tissue factor induction, treatment of endothelial cells with the Ca++ chelator BAPTA-AM, as well as the calcineurin inhibitor cyclosporin A, partially inhibited VEGF induced tissue factor upregulation. Furthermore, tissue factor reporter gene assays revealed a synergistic cooperation of NFAT and EGR-1 in the induction of the TF promoter, and a physical interaction between the two factors was indicated by co-immunoprecipitation assays. Another gene upregulated by VEGF predominantly via NFAT, which is not induced by EGF, is the DSCR-1 gene. The calcineurin inhibitor DSCR-1 seems to be induced by VEGF in a negative feed-back loop to limit NFAT activation. When we tested adenoviral overexpression of DSCR-1, VEGF-mediated induction of tissue factor mRNA was reduced, and complete suppression could be achieved by a combination of viruses expressing DSCR-1 and NAB2, a corepressor of EGR-1. These findings support that both, NFAT and EGR-1, are required for tissue factor upregulation in response to VEGF.
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Mora, Gloria R., Kenneth R. Olivier, John C. Cheville, Richard F. Mitchell, Wilma L. Lingle, and Donald J. Tindall. "The Cytoskeleton Differentially Localizes the Early Growth Response Gene-1 Protein in Cancer and Benign Cells of the Prostate." Molecular Cancer Research 2, no. 2 (February 1, 2004): 115–28. http://dx.doi.org/10.1158/1541-7786.115.2.2.
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Abstract Prostate cancer is the most prevalent malignancy and the second leading cause of cancer mortality in men. Early growth response gene-1 (EGR-1) plays a crucial role in the development and progression of prostate cancer. The presented data show that EGR-1 differs in cellular localization in benign cells compared with malignant prostate cells and that this localization is critical for the transcriptional activation of EGR-1-dependent genes. Immunohistochemistry of human prostate cancer specimens demonstrated higher levels of EGR-1 in malignant cells located predominantly in the cytoplasm, whereas benign cells contained lower levels of EGR-1 located predominantly in the nucleus. Benign prostate cells responded to mitogens in vitro, with increased levels of EGR-1, rapid nuclear translocation, and enhanced transcriptional activity, whereas malignant prostate cells did not exhibit the same responses, and the protein remained in the cytoplasm. The central aspect of this difference is the association of EGR-1 with microtubules, which is exclusive to the benign cells of the prostate and is requisite for the nuclear translocation and transcriptional activity of EGR-1. Our in vitro data demonstrate that the differences in EGR-1 between benign and malignant prostate cells extend beyond cellular levels, which was confirmed by immunohistochemistry in human tissues. Thus, we add the novel concept that microtubules regulate EGR-1 localization in benign prostate cells but not in malignant prostate cells.
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Cera, Arcangela Anna, Emanuele Cacci, Camilla Toselli, Silvia Cardarelli, Alessandra Bernardi, Roberta Gioia, Mauro Giorgi, Giancarlo Poiana, and Stefano Biagioni. "Egr-1 Maintains NSC Proliferation and Its Overexpression Counteracts Cell Cycle Exit Triggered by the Withdrawal of Epidermal Growth Factor." Developmental Neuroscience 40, no. 3 (2018): 223–33. http://dx.doi.org/10.1159/000489699.
Full textAbstract:
In adult mammals, neural stem cells (NSCs) reside in specialized niches at the level of selected CNS regions, such as the subventricular zone (SVZ). The signaling pathways that regulate NSC proliferation and differentiation remain poorly understood. Early growth response protein 1 (Egr-1) is an important transcription factor, widely studied in the adult mammalian brain, mediating the activation of target genes by a variety of extracellular stimuli. In our study, we aimed at testing how Egr-1 regulates adult NSCs derived from mouse SVZ and, in particular, the interplay between Egr-1 and the proliferative factor EGF. We demonstrate that Egr-1 expression in NSCs is induced by growth factor stimulation, and its level decreases after EGF deprivation or by using AG1478, an inhibitor of the EGF/EGFR signaling pathway. We also show that Egr-1 overexpression rescues the cell proliferation decrease observed either after EGF removal or upon treatment with AG1478, suggesting that Egr-1 works downstream of the EGF pathway. To better understand this mechanism, we investigated targets downstream of both the EGF pathway and Egr-1, and found that they regulate genes involved in NSC proliferation, such as cell cycle regulators, cyclins, and cyclin-dependent kinase inhibitors.
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Yao, Hui-Wen, Shih-Heng Chen, Ching Li, Yuk-Ying Tung, and Shun-Hua Chen. "Suppression of Transcription Factor Early Growth Response 1 Reduces Herpes Simplex Virus 1-Induced Corneal Disease in Mice." Journal of Virology 86, no. 16 (May 30, 2012): 8559–67. http://dx.doi.org/10.1128/jvi.00505-12.
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Herpes simplex virus 1 replication initiates angiogenesis and inflammation in the cornea. This can result in herpetic stromal keratitis (HSK), which is a leading cause of infection-induced corneal blindness. Host cellular factors mediate the progression of HSK, but little is known about these cellular factors and their mechanisms of action. We show here that the expression of the cellular transcription factor early growth response 1 (Egr-1) in HSV-1-infected mouse corneas was enhanced. Enhanced Egr-1 expression aggravated HSK by increasing viral replication and subsequent neovascularization with high levels of potent angiogenic factors, fibroblast growth factor 2, and vascular endothelial growth factor. Furthermore, Egr-1 deficiency due to a targeted disruption of the gene or knockdown of Egr-1 expression topically using a DNA-based enzyme significantly reduced HSK by decreasing both viral replication and the angiogenic response. The present study provides the first evidence that endogenous Egr-1 aggravates HSK and that blocking Egr-1 reduces corneal damage.
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Clarkson, Richard W. E., Catherine A. Shang, Linda K. Levitt, Tammy Howard, and Michael J. Waters. "Ternary Complex Factors Elk-1 and Sap-1a Mediate Growth Hormone-Induced Transcription of Egr-1 (Early Growth Response Factor-1) in 3T3-F442A Preadipocytes." Molecular Endocrinology 13, no. 4 (April 1, 1999): 619–31. http://dx.doi.org/10.1210/mend.13.4.0266.
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Abstract In our search for transcription factors induced by GH, we have analyzed immediate early gene activation in a model of GH-dependent differentiation. Here we describe the activation of early growth response factor-1 (egr-1) in GH-stimulated 3T3-F442A preadipocytes and the transcription factors responsible for its transactivation. Binding activity of egr-1 in electrophoretic mobility shift assay (EMSA) increased transiently 1 h after GH stimulation, accompanied by a concomitant increase in egr-1 mRNA. egr-1 induction appeared not to be related to proliferation since it was amplified in quiescent preadipocytes at a time when cells were refractive to GH-stimulated DNA synthesis. Truncations of the proximal 1 kb of the egr-1 promoter revealed that a 374-bp region (−624 to −250) contributes about 80% of GH inducibility in 3T3-F442A cells and approximately 90% inducibility in CHO-K1 cells. This region contains three juxtaposed SRE (serum response element)/Ets site pairs known to be important for egr-1 activity in response to exogenous stimuli. Site-specific mutations of individual SRE and Ets sites within this region each reduced GH inducibility of the promoter. Use of these site-specific mutations in EMSA showed that disruption of either Ets or SRE sites abrogated ternary complex formation at the composite sites. DNA binding of ternary complexes, but not binary complexes, in EMSA was rapidly and transiently increased by GH. EMSA supershifts indicated these ternary complexes contained serum response factor (SRF) and the Ets factors Elk-1 and Sap-1a. Coexpression of Sap-1a and Elk-1 resulted in a marked increase in GH induction of egr-1 promoter activity, although transfection with expression vectors for either Ets factor alone did not significantly enhance the GH response. We conclude that GH stimulates transcription of egr-1 primarily through activation of these Ets factors at multiple sites on the promoter and that stabilization of ternary complexes with SRF at these sites maximizes this response.
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SILVERMAN, Eric S., Jing DU, Amy J. WILLIAMS, Raj WADGAONKAR, Jeffrey M. DRAZEN, and Tucker COLLINS. "cAMP-response-element-binding-protein-binding protein (CBP) and p300 are transcriptional co-activators of early growth response factor-1 (Egr-1)." Biochemical Journal 336, no. 1 (November 15, 1998): 183–89. http://dx.doi.org/10.1042/bj3360183.
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Egr-1 (early-growth response factor-1) is a sequence-specific transcription factor that plays a regulatory role in the expression of many genes important for cell growth, development and the pathogenesis of disease. The transcriptional co-activators CBP (cAMP-response-element-binding-protein-binding protein) and p300 interact with sequence-specific transcription factors as well as components of the basal transcription machinery to facilitate RNA polymerase II recruitment and transcriptional initiation. Here we demonstrate a unique way in which Egr-1 physically and functionally interacts with CBP/p300 to modulate gene transcription. CBP/p300 potentiated Egr-1 mediated expression of 5-lipoxygenase (5-LO) promoter–reporter constructs, and the degree of trans-activation was proportional to the number of Egr-1 consensus binding sites present in wild-type and naturally occurring mutants of the 5-LO promoter. The N- and C-terminal domains of CBP interact with the transcriptional activation domain of Egr-1, as demonstrated by a mammalian two-hybrid assay. Direct protein–protein interactions between CBP/p300 and Egr-1 were demonstrated by glutathione S-transferase fusion-protein binding and co-immunoprecipitation/Western-blot studies. These data suggest that CBP and p300 act as transcriptional co-activators for Egr-1-mediated gene expression and that variations between individuals in such co-activation could serve as a genetic basis for variability in gene expression.
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Bouchard, Frédéric, Simon D. Bélanger, Katherine Biron-Pain, and Yves St-Pierre. "EGR-1 activation by EGF inhibits MMP-9 expression and lymphoma growth." Blood 116, no. 5 (August 5, 2010): 759–66. http://dx.doi.org/10.1182/blood-2009-12-257030.
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Abstract Progression of hematologic malignancies is strongly dependent on bidirectional interactions between tumor cells and stromal cells. Expression of members of the matrix metalloproteinase (MMP) family by stromal cells is a central event during these interactions. However, although several studies have focused on the mechanisms responsible for induction of MMP in stromal cells, the signals that negatively regulate their secretion of in these cells remain largely unknown. Here, we provide evidence that MMP-9 production by stromal cells is suppressed through activation of early growth response protein 1 (EGR-1), thereby inhibiting the growth of thymic lymphoma. We found that EGR-1 expression is induced in stromal cells after contact with lymphoma cells via epidermal growth factor (EGF). Moreover, development of thymic lymphoma was inhibited when induced by lymphoma cells overexpressing EGF compared with control lymphoma cells. Using transgenic mice containing MMP-9 promoter-driven luciferase transgene in its genome, we further demonstrated that EGF/EGR-1 repressed transcriptional activation of the MMP-9 gene by stromal cells. De novo expression of EGR-1 alone by gene transfer or exposure to recombinant human EGF also inhibited MMP-9 expression. Taken together, these results indicate that EGR-1 could be a source of novel targets for therapeutic intervention in lymphoid tumors in which MMP-9 plays a critical role.
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Saben, Jessica, Ying Zhong, Horacio Gomez-Acevedo, Keshari M. Thakali, Sarah J. Borengasser, Aline Andres, and Kartik Shankar. "Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity." American Journal of Physiology-Endocrinology and Metabolism 305, no. 1 (July 1, 2013): E1—E14. http://dx.doi.org/10.1152/ajpendo.00076.2013.
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Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a proinflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Here, we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNFα treatment and gene/protein expression analyses of MAPK pathways and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate early response in cytotrophoblasts in response to palmitic acid (PA), TNFα, or a combination of both (PA + TNFα). Both gene ontology and gene set enrichment analysis revealed MAPK and EGR-1 signaling to be upregulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased proinflammatory cytokine ( IL-6, TNFα, and IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK-responsive immediate early factors on the EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters ( IL-6, TNFα, and IL-8) and an impaired proinflammatory response following knockdown of EGR-1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK/EGR-1 signaling.
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Dinkel, Adelheid, Klaus Warnatz, Birgit Ledermann, Antonius Rolink, Peter F. Zipfel, Kurt Bürki, and Hermann Eibel. "The Transcription Factor Early Growth Response 1 (Egr-1) Advances Differentiation of Pre-B and Immature B Cells." Journal of Experimental Medicine 188, no. 12 (December 21, 1998): 2215–24. http://dx.doi.org/10.1084/jem.188.12.2215.
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In mature B lymphocytes, the zinc finger transcription factor early growth response 1 (Egr-1) is one of the many immediate-early genes induced upon B cell antigen receptor engagement. However, its role during earlier stages of lymphopoiesis has remained unclear. By examining bone marrow B cell subsets, we found Egr-1 transcripts in pro/pre-B and immature B lymphocytes, and Egr-1 protein in pro/pre-B–I cells cultivated on stroma cells in the presence of interleukin (IL)-7. In recombinase-activating gene (RAG)-2–deficient mice overexpressing an Egr-1 transgene in the B lymphocyte lineage, pro/pre-B–I cells could differentiate past a developmental block at the B220low BP-1− stage to the stage of B220low BP-1+ pre-B–I cells, but not further to the B220low BP-1+ CD25+ stage of pre-B–II cells. Therefore, during early B lymphopoiesis progression from the B220low BP-1− IL-2R− pro/pre-B–I stage to the B220low BP-1+ IL-2R+ pre-B–II stage seems to occur in at least two distinct steps, and the first step to the stage of B220low BP-1+ pre-B–I cells can be promoted by the overexpression of Egr-1 alone. Wild-type mice expressing an Egr-1 transgene had increased proportions of mature immunoglobulin (Ig)M+ B220high and decreased proportions of immature IgM+ B220low bone marrow B cells. Since transgenic and control precursor B cells show comparable proliferation patterns, overexpression of Egr-1 seems also to promote entry into the mature B cell stage. Analysis of changes in the expression pattern of potential Egr-1 target genes revealed that Egr-1 enhances the expression of the aminopeptidase BP-1/6C3 in pre-B and immature B cells and upregulates expression of the orphan nuclear receptor nur77 in IgM+ B cells.
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Chen, Lijuan, Siqing Wang, Yiming Zhou, Xiaosong Wu, Igor Entin, Joshua Epstein, Shmuel Yaccoby, et al. "Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma." Blood 115, no. 1 (January 7, 2010): 61–70. http://dx.doi.org/10.1182/blood-2009-03-210526.
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Abstract Tumor–bone marrow microenvironment interactions in multiple myeloma (MM) are documented to play crucial roles in plasma-cell growth/survival. In vitro coculture of MM cells with osteoclasts supported cell survival and significantly down-regulated JUN expression. JUN expression in myeloma cells from late-stage and high-risk MM was significantly lower than in plasma cells from healthy donors, monoclonal gammopathy of undetermined significance, smoldering MM, and low-risk MM; patients with low-JUN–expressing MM cells had earlier disease-related deaths. JUN overexpression in MM cells induced cell death and growth inhibition and up-regulated expression of early growth response protein 1 (EGR-1), whose low expression also carried unfavorable clinical implications. EGR-1 knockdown in MM cells abrogated JUN overexpression-induced MM cell death and growth inhibition, indicating that EGR-1 acts directly downstream of JUN. JUN modulates myeloma cell apoptosis through interacting with EGR-1, which down-regulates Survivin and triggers caspase signaling. Importantly, high JUN or EGR-1 expression was associated with improved outcome in Total Therapy 3, in which bortezomib is given throughout therapy, versus Total Therapy 2, in which bortezomib is given only at relapse. Consistently, JUN or EGR-1 knockdown in cultured MM cells enhanced their resistance to bortezomib, demonstrating the crucial role of low JUN/EGR-1 expression in MM resistance to bortezomib.
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Liang, Jinlong, Jingyi Wang, Jinshui Zeng, Zhibo Bai, Zhiyuan Zheng, Yue Zheng, Fengqi Jiang, and Di Wu. "The Landscape of Early Growth Response Family Members 1-4 in Hepatocellular Carcinoma: Their Biological Roles and Diagnostic Utility." Disease Markers 2022 (August 22, 2022): 1–8. http://dx.doi.org/10.1155/2022/3144742.
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The incidence of hepatocellular carcinoma (HCC), which is one of the most frequent types of cancer seen all over the world, is steadily growing from year to year. EGR genes are members of the early growth response (EGR) gene family. It has been shown that EGR genes play an increasingly essential role in the development of tumors and the progression of numerous malignancies. However, the possible diagnostic and prognostic roles of EGR genes in HCC have only been examined in a limited number of studies. Expression and methylation data on EGR family members were obtained from TCGA datasets. The prognostic values of EGR members were studied. Additionally, the correlations of EGR members with immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA). In this study, we found that the expression of EGR1, EGR2, EGR3, and EGR4 was distinctly decreased in HCC specimens compared with nontumor specimens. ROC assays confirmed that they have a strong ability in screening HCC specimens from nontumor specimens. According to the findings of Pearson’s correlation, EGR1, EGR2, EGR3, and EGR4 were found to have a negative association with the methylation level. Survival study revealed that EGR1, EGR2, and EGR3 were associated with the clinical outcome of HCC patients. Immune cell enrichment analysis demonstrated that the expressions of all EGR members were positively related to the levels of most types of immune cells, such as macrophages, NK cells, B cells, T cells, eosinophils, and CD8 T cells. Overall, the current work demonstrated the expression mode and prognostic value of EGR members in HCC in a comprehensive manner, offering insights for further research of the EGR family as possible clinical biomarkers in HCC.
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Sayasith, Khampoune, Kristy A. Brown, Jacques G. Lussier, Monique Doré, and Jean Sirois. "Characterization of bovine early growth response factor-1 and its gonadotropin-dependent regulation in ovarian follicles prior to ovulation." Journal of Molecular Endocrinology 37, no. 2 (October 2006): 239–50. http://dx.doi.org/10.1677/jme.1.02078.
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Early growth response factor-1 (EGR-1) is a transcription factor that is involved in the transactivation of several genes. The objective of this study was to characterize gonadotropin-dependent regulation of bovine EGR-1 in preovulatory follicles prior to ovulation. Bovine EGR-1 cDNA was obtained by RT-PCR, 5′- and 3′-RACE, its open reading frame composed of 1623 bp, and its coding region encodes a 540-amino acid protein that displays 62–93% identity to known mammalian homologs. The regulation of EGR-1 mRNA was studied in bovine preovulatory follicles which were isolated 0–24 h post-hCG using semiquantitative RT-PCR/Southern blot. Results revealed that the levels of EGR-1 mRNA were very low in follicles at 0 h, markedly increased at 6 h (P < 0.05) when compared to 0 h, and decreased between 12 and 24 h post-hCG. High levels of the EGR-1 mRNA were also observed in corpus luteum, uterus, kidney, pituitary, and spleen, moderate and low in other bovine tissues tested. Analyses performed on isolated preparations of granulosa and theca cells indicated that EGR-1 mRNA was regulated in both cell types, with a predominant expression in granulosa cells. Immunohistochemistry on sections of preovulatory follicles isolated before and after hCG confirmed its protein expression in granulosa cells, 24 h post-hCG. Studies of EGR-1 regulation in primary granulosa cells cultured with forskolin showed that levels of EGR-1 mRNA were low at 0 h, highly increased at 6 h post-forskolin (P < 0.05), and declined to steady state thereafter. Immunoblotting confirmed forskolin-induced EGR-1 protein in cultures. Interestingly, overexpression of EGR-1 increased the levels of mRNA for prostaglandin (PG) G/H synthase-2 (PGHS-2), PG E synthase (PGES), PG E2 receptor (EP2), LH receptor (LH-R), but not for cytochrome P450-side chain cleavage (P450scc), and cytochrome P450 aromatase (P450arom) in granulosa cultures. Thus, this study reports for the first time, a gonadotropin-dependent induction of follicular EGR-1 prior to ovulation in large monoovulatory species and its stimulating effect on the expression of genes known to be involved in prostaglandin biosynthesis pathway, thereby suggesting its potential involvement in the regulation of preovulatory events in cattle.
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Edgley, Amanda J., Nancy R. Nichols, and Warwick P. Anderson. "Acute intrarenal infusion of ANG II does not stimulate immediate early gene expression in the kidney." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 282, no. 4 (April 1, 2002): R1133—R1139. http://dx.doi.org/10.1152/ajpregu.00187.2001.
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ANG II is capable of stimulating expression of immediate early genes such as egr-1 and c- fos in a variety of cultured cells, including cells of renal origin. To investigate whether ANG II can stimulate early growth response gene expression in vivo, we studied the effects of acute renal artery infusion of low-dose ANG II (2.5 ng · kg−1 · min−1) or vehicle on the renal expression of c- fos and egr-1 genes in rats. ANG II infusion for 30 or 240 min decreased renal vascular conductance by ∼13 and 8%, respectively, compared with the vehicle group. Expression of the early growth response genes c-fosand egr-1 was analyzed using Northern blot hybridization. No significant upregulation of c- fos or egr-1 mRNA levels was detected in rats that received ANG II for either 30 or 240 min, compared with the vehicle groups. We conclude that ANG II, at doses that cause significant physiological effects, does not increase the renal expression of c- fos or egr-1 genes over periods of up to 4 h in vivo.
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Jeon, Hyun Min, Su Yeon Lee, Min Kyung Ju, Hye Gyeong Park, and Ho Sung Kang. "Early Growth Response 1 Induces Epithelial-to-mesenchymal Transition via Snail." Journal of Life Science 23, no. 8 (August 30, 2013): 970–77. http://dx.doi.org/10.5352/jls.2013.23.8.970.
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Wagner, Mandy, Karin Schmelz, Bernd Dörken, and Ingo Tamm. "Transcriptional regulation of humansurvivinby early growth response (Egr)-1 transcription factor." International Journal of Cancer 122, no. 6 (November 20, 2007): 1278–87. http://dx.doi.org/10.1002/ijc.23183.
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Landesberg, Leonard J., Ramachandran Ramalingam, Kenneth Lee, Todd K. Rosengart, and Ronald G. Crystal. "Upregulation of transcription factors in lung in the early phase of postpneumonectomy lung growth." American Journal of Physiology-Lung Cellular and Molecular Physiology 281, no. 5 (November 1, 2001): L1138—L1149. http://dx.doi.org/10.1152/ajplung.2001.281.5.l1138.
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In the adult rodent, pneumonectomy results in compensatory lung growth characterized by cell proliferation. The molecular mechanisms governing this response remain unknown. We hypothesized that, in the early period postpneumonectomy, upregulated expression of transcription factors drives the growth process. We utilized a cDNA expression array to screen for upregulated transcription factors after left pneumonectomy in adult C57BL/6 mice, using unoperated mice as controls. Quantification of mRNA expression in the remaining lung at 2 h demonstrated a twofold or greater upregulation of six transcription factors: early growth response gene-1 (Egr-1), Nurr77, tristetraprolin, the primary inhibitor of nuclear factor-κB (IκB-α), gut-enriched Krüppel-like factor (GKLF), and LRG-21. Northern analysis was used to quantify the upregulation of expression of these genes relative to sham thoracotomy and unoperated controls. The largest increase was in Egr-1 (4.7-fold > naive). Time-course analysis over the first 24 h confirmed the transient nature of the early upregulation. In the context that postpneumonectomy lung growth is associated with cell proliferation and that genes such as Egr-1, Nurr77, LRG-21, and tristetraprolin have known roles in stress response, vascular biology, embryology, and cellular development, these data support the concept that transcription factors function early in the cascade of events leading to the compensatory response.
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Liu, Chengwei, Xuesong Zhang, Shi Wang, Mingxun Cheng, Chuanyu Liu, Shuqing Wang, Xinhua Hu, and Qiang Zhang. "Transfected Early Growth Response Gene-1 DNA Enzyme Prevents Stenosis and Occlusion of Autogenous Vein GraftIn Vivo." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/310406.
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The aim of this study was to detect the inhibitory action of the early growth response gene-1 DNA enzyme (EDRz) as a carrying agent by liposomes on vascular smooth muscle cell proliferation and intimal hyperplasia. An autogenous vein graft model was established. EDRz was transfected to the graft vein. The vein graft samples were obtained on each time point after surgery. The expression of the EDRz transfected in the vein graft was detected using a fluorescent microscope. Early growth response gene-1 (Egr-1) mRNA was measured using reverse transcription-PCR andin situhybridization. And the protein expression of Egr-1 was detected by using western blot and immunohistochemistry analyses. EDRz was located at the media of the vein graft from 2 to 24 h, 7 h after grafting. The Egr-1 protein was mainly located in the medial VSMCs, monocytes, and endothelium cells during the early phase of the vein graft. The degree of VSMC proliferation and thickness of intima were obviously relieved compared with the no-gene therapy group. EDRz can reduce Egr-1 expression in autogenous vein grafts, effectively restrain VSMC proliferation and intimal hyperplasia, and prevent vascular stenosis and occlusion after vein graft.
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Guo, Lili, Maria Dolors Sans, Grzegorz T. Gurda, Sae-Hong Lee, Stephen A. Ernst, and John A. Williams. "Induction of early response genes in trypsin inhibitor-induced pancreatic growth." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 2 (February 2007): G667—G677. http://dx.doi.org/10.1152/ajpgi.00433.2006.
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Endogenous CCK release induced by a synthetic trypsin inhibitor, camostat, stimulates pancreatic growth; however, the mechanisms mediating this growth are not well established. Early response genes often couple short-term signals with long-term responses. To study their participation in the pancreatic growth response, mice were fasted for 18 h and refed chow containing 0.1% camostat for 1–24 h. Expression of 18 early response genes were evaluated by quantitative PCR; mRNA for 17 of the 18 increased at 1, 2, 4, or 8 h. Protein expression for c-jun, c-fos, ATF-3, Egr-1, and JunB peaked at 2 h. Nuclear localization was confirmed by immunohistochemistry of c-fos, c-jun, and Egr-1. Refeeding regular chow induced only a small increase of c-jun and none in c-fos expression. JNKs and ERKs were activated 1 h after camostat feeding as was the phosphorylation of c-jun and ATF-2. AP-1 DNA binding evaluated by EMSA showed a significant increase 1–2 h after camostat feeding with participation of c-jun, c-fos, ATF-2, ATF-3, and JunB shown by supershift. The CCK antagonist IQM-95,333 blocked camostat feeding-induced c-jun and c-fos expression by 67 and 84%, respectively, and AP-1 DNA binding was also inhibited. In CCK-deficient mice, the maximal response of c-jun induction and AP-1 DNA binding were reduced by 64 and 70%, respectively. These results indicate that camostat feeding induces a spectrum of early response gene expression and AP-1 DNA binding and that these effects are mainly CCK dependent.
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Brennan, Eoin P., Muthukumar Mohan, Aaron McClelland, Christos Tikellis, Mark Ziemann, Antony Kaspi, Stephen P. Gray, et al. "Lipoxins Regulate the Early Growth Response–1 Network and Reverse Diabetic Kidney Disease." Journal of the American Society of Nephrology 29, no. 5 (February 28, 2018): 1437–48. http://dx.doi.org/10.1681/asn.2017101112.
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Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation.Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE−/− mice treated with streptozotocin.Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF-α, IL-1β, NF-κB). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response–1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF-α–driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α.Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.
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Thulasingam, Senthilkumar, Sundar Krishnasamy, David Raj C., Manuel Lasch, Srinivasan Vedantham, and Elisabeth Deindl. "Insulin Treatment Forces Arteriogenesis in Diabetes Mellitus by Upregulation of the Early Growth Response-1 (Egr-1) Pathway in Mice." International Journal of Molecular Sciences 20, no. 13 (July 5, 2019): 3320. http://dx.doi.org/10.3390/ijms20133320.
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The process of arteriogenesis is severely compromised in patients with diabetes mellitus (DM). Earlier studies have reported the importance of Egr-1 in promoting collateral outward remodeling. However, the role of Egr-1 in the presence of DM in outward vessel remodeling was not studied. We hypothesized that Egr-1 expression may be compromised in DM which may lead to impaired collateral vessel growth. Here, we investigated the relevance of the transcription factor Egr-1 for the process of collateral artery growth in diabetic mice. Induction of arteriogenesis by femoral artery ligation resulted in an increased expression of Egr-1 on mRNA and protein level but was severely compromised in streptozotocin-induced diabetic mice. Diabetes mellitus mice showed a significantly reduced expression of Egr-1 endothelial downstream genes Intercellular Adhesion Molecule-1 (ICAM-1) and urokinase Plasminogen Activator (uPA), relevant for extravasation of leukocytes which promote arteriogenesis. Fluorescent-activated cell sorting analyses confirmed reduced leukocyte recruitment. Diabetes mellitus mice showed a reduced expression of the proliferation marker Ki-67 in growing collaterals whose luminal diameters were also reduced. The Splicing Factor-1 (SF-1), which is critical for smooth muscle cell proliferation and phenotype switch, was found to be elevated in collaterals of DM mice. Treatment of DM mice with insulin normalized the expression of Egr-1 and its downstream targets and restored leukocyte recruitment. SF-1 expression and the diameter of growing collaterals were normalized by insulin treatment as well. In summary, our results showed that Egr-1 signaling was impaired in DM mice; however, it can be rescued by insulin treatment.
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Krishnaraju, Kandasamy, Barbara Hoffman, and Dan A. Liebermann. "Early growth response gene 1 stimulates development of hematopoietic progenitor cells along the macrophage lineage at the expense of the granulocyte and erythroid lineages." Blood 97, no. 5 (March 1, 2001): 1298–305. http://dx.doi.org/10.1182/blood.v97.5.1298.
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Using a variety of differentiation-inducible myeloid cell lines, we previously showed that the zinc-finger transcription factor early growth response gene 1 (Egr-1) is a positive modulator of macrophage differentiation and negatively regulates granulocytic differentiation. In this study, high-efficiency retroviral transduction was used to ectopically express Egr-1 in myeloid-enriched or stem cell–enriched bone marrow cultures to explore its effect on the development of hematopoietic progenitors in vitro and in lethally irradiated mice. It was found that ectopic Egr-1 expression in normal hematopoietic progenitors stimulates development along the macrophage lineage at the expense of development along the granulocyte or erythroid lineages, regardless of the cytokine used. Moreover, Egr-1 accelerated macrophage development by suppressing the proliferative phase of the growth-to-macrophage developmental program. The remarkable ability of Egr-1 to dictate macrophage development at the expense of development along other lineages resulted in failure of Egr-1–infected hematopoietic progenitors to repopulate the bone marrow and spleen, and thereby prevent death, in lethally irradiated mice. These observations further highlight the role Egr-1 plays in monocytic differentiation and growth suppression.