Disease relevance of Egr1

• Early growth response (EGR) transactivators act as critical regulators of several physiological processes, including peripheral nerve myelination and progression of prostate cancer [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 [2].
• The S1P-induced Egr-1 expression was partially inhibited by treatment of the cells with either calphostin C, an inhibitor of protein kinase C (PKC), or pertussis toxin (PTX), and completely inhibited by the combination of these agents [3].
• Egr-1 in turn might play an important role in up-regulating the expression of endo-bFGF which overlapped with the expression of bFGFR to ensure the combination of ligand and receptor to protect against brain ischemia [4].
• The NGFI-A gene encodes a "zinc-finger" protein that is rapidly induced by nerve growth factor (NGF) in PC12 rat pheochromocytoma cells [5].

Psychiatry related information on Egr1

• Exposure to lead elevates induction of zif268 and Arc mRNA in rats after electroconvulsive shock: the involvement of protein kinase C [6].
• Induction of hippocampal long-term potentiation during waking leads to increased extrahippocampal zif-268 expression during ensuing rapid-eye-movement sleep [7].
• Activation of the cGMP pathway in dopaminergic structures reduces cocaine-induced EGR-1 expression and locomotor activity [8].
• We found that the expression of Fos and NGFI-A was markedly increased in the locus coeruleus and other brain areas both after spontaneous wakefulness and after short periods (3-24 h) of sleep deprivation [9].
• Several Fos-positive cells and most NGFI-A positive cells found in the locus coeruleus after periods of spontaneous wakefulness were shown to be noradrenergic [9].

High impact information on Egr1

• Here we show that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5' untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices [10].
• Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters [10].
• Here we targeted Egr-1 using a new class of DNA-based enzyme that specifically cleaved Egr-1 mRNA, blocked induction of Egr-1 protein, and inhibited cell proliferation and wound repair in culture [11].
• New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth after injury [11].
• The DNA enzyme also inhibited Egr-1 induction and neointima formation after balloon injury to the rat carotid artery wall [11].

Chemical compound and disease context of Egr1

• 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 [2].
• Influence of high salt culture conditions on the expression of immediate early gene egr-1 in rat C6 glioma cells was investigated by measuring both Egr-1 mRNA and protein levels in the cells exposed to the medium containing high concentrations of NaCl [12].
• Prostaglandin G/H synthase-2 and zif-268 mRNA expression is transiently induced in rat brain by kainic acid (KA)-induced seizures and by a single electroconvulsive shock [13].
• Studies with norepinephrine in combination with various adrenergic receptor antagonists revealed that the induction of Egr-1 is primarily an alpha 1-mediated, pertussis toxin-insensitive response [14].
• FK 409 ameliorates small-for-size liver graft injury by attenuation of portal hypertension and down-regulation of Egr-1 pathway [15].

Biological context of Egr1

• Expression of the Egr1 protein in PC12 cells stimulates the chloramphenicol acetyltransferase reporter gene placed under the control of the first 272 nucleotides of the rat TH promoter [16].
• An oligonucleotide encompassing the AP-1/E-box sequence of the rat TH promoter competes in electrophoretic mobility shift assays for binding of nuclear extracts from control and TPA-treated cells to an oligonucleotide containing the Sp1/Egr1 element, indicating that these two enhancers may interact [16].
• Transfection of PC12 cells with Fra-2 induced reporter activity requiring the AP1, but not the Egr1 motif [17].
• However, when cotransfected with Fra-2, Egr1 expression plasmids elicited lower induction of luciferase activity than observed with Egr1 alone [17].
• Egr-1 competes with Sp1 for overlapping binding sites even when the former is at a stoichiometric disadvantage [18].

Anatomical context of Egr1

• Treatment of PC12 cells with phorbol ester (2 micrometer 12-O-tetradecanoylphorbol-13-acetate (TPA)) gives rise to a new Egr1-containing complex [16].
• In contrast, extracts from the adrenal medulla of IMO-treated rats form a novel complex (II) that contains the Egr1 protein [19].
• Activity-dependent expression of Egr1 mRNA in somatosensory cortex of developing rats [20].
• Role for early growth response-1 protein in alpha(1)-adrenergic stimulation of fibroblast growth factor-2 promoter activity in cardiac myocytes [21].
• The induction of Egr-1 in rat neonatal ventricular myocytes with phorbol-12-myristate-13-acetate or in HeLa S3 cells by regulated expression of Egr-1 in a tetracycline-responsive promoter, suppressed expression from the beta(1)-AR promoter [22].

Associations of Egr1 with chemical compounds

• Using gel mobility shift assays, we observed a transient increase in a complex between nuclear extracts from neonatal rat cardiac myocytes treated with inducers of Egr-1, including the alpha-adrenergic agonist phenylephrine, angiotensin II, and phorbol ester, and a consensus Egr-1 DNA element [21].
• Angiotensin II (1, 10, 100 ng) induced a dose-dependent expression of c-Fos and Krox-24 in the subfornical organ, the median preoptic area and in the paraventricular nucleus and supraoptic nucleus of the hypothalamus, regions known to be involved in the central osmoregulatory and neuroendocrine actions of angiotensin II [23].
• 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 [2].
• 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 [2].
• Membrane depolarization selectively induced a sustained increase in early growth response-1 (Egr-1) mRNA and protein, which were inhibited by the VDCC blocker nimodipine and the SOCC inhibitor 2-aminoethoxydiphenylborate (2-APB) [24].

Physical interactions of Egr1

• In conclusion, the findings demonstrate that Egr-1 actually binds to the regulatory upstream region of the LH receptor gene and positively regulates receptor gene expression [25].
• NGFI-A-binding protein 2 (NAB2) is an example of a negative transcriptional cofactor capable of binding directly to Egr-1 and repressing Egr-1-mediated transcription [26].
• Mutations that abolish the Sp1 binding activity also impair the transactivation of the NGFI-A promoter by COUP-TF [27].
• Differences in the DNA methylation pattern between the offspring of High and Low licking/grooming--arched-back mothers emerge over the first week of life, are reversed with cross-fostering, persist into adulthood and are associated with altered histone acetylation and transcription factor (NGFI-A) binding to the glucocorticoid receptor promoter [28].
• The promoter region of the NMDAR-1 receptor has a cis-regulatory element that is capable of binding to the NGFI-A family of transcription factors [29].

Enzymatic interactions of Egr1

• Moreover, on treatment with NGF, Trk-A is phosphorylated and early responsive genes such as NGFI-A, c-fos and c-jun are induced [30].

Regulatory relationships of Egr1

• Early growth response gene-1 regulates the expression of the rat luteinizing hormone receptor gene [25].
• The S1P-induced expression of Egr-1 was also completely inhibited in association with complete inhibition of ERK by PD 98059, an ERK kinase inhibitor [3].
• Ability of Egr1 to activate tyrosine hydroxylase transcription in PC12 cells. Cross-talk with AP-1 factors [16].
• In conclusion, Sp1 positively regulates while Egr-1 negatively regulates the rat pgp2/mdr1b gene [31].
• These data, together with our previous demonstration that 50% of SRIF-positive neurons in the PeN coexpress Egr-1 after photic stimulation, suggest that activation of SRIF neurons in the PeN may entrain the episodes of GH secretion to the dark/light interface [32].

Other interactions of Egr1

• This may, however, reflect redundancy in the control of FGF-2 promoter activity as our data support a stimulatory role for Egr-1 and Sp1 [33].
• The phyto-chemical (-)-epigallocatechin gallate suppresses gene expression of epidermal growth factor receptor in rat hepatic stellate cells in vitro by reducing the activity of Egr-1 [34].
• Here we demonstrate for the first time that cysteamine increases the expression and nuclear translocation of Egr-1, Ref-1, and Trx, and activates binding of Egr-1 to DNA [35].
• The Egr-1 and Sp1 binding sites are partially overlapping and their binding sequence is conserved among mammalian beta(1)-AR genes [22].
• MK801 did not inhibit Krox-24 expression in granule neurons or the delayed expression of Fos, Jun-D and Krox-24 in hilar interneurons [36].

Analytical, diagnostic and therapeutic context of Egr1

• Site-directed mutagenesis of either the Sp1/Egr1 motif or of an upstream AP-1 motif or both abolishes the Egr1-mediated induction of chloramphenicol acetyltransferase activity [16].
• Sp1/Egr1 motif: a new candidate in the regulation of rat tyrosine hydroxylase gene transcription by immobilization stress [19].
• Egr1 mRNA was measured with in situ hybridization at postnatal Day (P) 6, P9, P12, P15, and P21 [20].
• In differentiated granulosa cells that had been pretreated with FSH for 48 h, the levels of both mRNA and Egr-1 protein were induced by hCG or cAMP, reaching maximal levels approximately 1.5 h after treatment and then returning to basal levels 8 h thereafter [25].
• In C6 cells, Western blotting showed that S1P also induced expression of early growth response-1 (Egr-1), one of the immediate early gene products and an essential transcriptional factor for FGF-2 expression [3].

References