History

EGR1 was identified in 1985 as a 3.4 kb mRNA showing rapid differential expression in cultured human peripheral blood mononuclear cells that had been treated with the lectin, Concanavalin-A, and cycloheximide [1]. It was one of a set of putative G0/G1 switch (G0S) regulatory genes (and was named G0S30). A close sequence similarity to the mRNAs of rat NGF1A and mouse Krox24 was reported in 1990 [2]. Rapid induction by Concanavalin-A alone was reported in 1996, as was an apparent inhibition by "stealth" concentrations (50 nM) of a complementary oligonucleotide . The ineffectiveness of higher oligonucleotide concentrations was deemed due to activation of an intracellular defense system against foreign nucleic acids [3]. In 1997 EGR1/G0S30 was reported to be one of several genes whose transcripts increase in "stressed" cells (i.e. the stress of isolation of the cells from human subjects). The cells had first to be "rested" in culture for 24 h in order to demonstrate most clearly the brisk (30 min) elevation of mRNA in response to Concanavalin-A [4]. It was speculated that the stress response is part of a pan-genic (and pan-nongenic) transcriptional response directed at foreign nucleic acids [5].

Disease relevance of EGR1

• The EGR1 gene was not deleted in nine other patients with acute myeloid leukemia who did not have abnormalities of chromosome 5 [6].
• In a majority of prostate cancers, EGR1 is overexpressed and promotes prostate tumor progression [7].
• In contrast, in other tumor types such as breast cancers and glioblastomas, EGR1 is expressed at low levels and when overexpressed can inhibit tumor growth [7].
• Adjacent binding sites for early growth response factor-1 (EGR1) and TATA box-binding protein (TBP) were identified on the herpes simplex virus latency promoter in previous work [8].
• These included a subgroup of transcription factors, including EGR1 and JUN, suggesting they play a specific role in the HIV-1 life cycle [9].

Psychiatry related information on EGR1

• Expression of the transcription factor Zif268 in the temporal cortex of monkeys during visual paired associate learning [10].
• By contrast, the patchy expression of Zif268 was not observed during another type of learning, visual discrimination learning [10].
• Expression of the immediate-early gene-encoded protein Egr-1 (zif268) during in vitro classical conditioning [11].
• We found that Zif268, a transcription factor regulated by neuronal activity, accumulated in patches in the anterior temporal lobe during visual stimulus-stimulus association learning, whereas other transcription factors, c-Fos and JunD, were not [10].

High impact information on EGR1

• The amino acid sequence of the predicted polypeptide shows significant homology to two growth regulated mammalian polypeptides, EGR1 and EGR2 [12].
• This structure-based strategy was tested by construction of a fusion protein, ZFHD1, that contained zinc fingers 1 and 2 from Zif268, a short polypeptide linker, and the homeodomain from Oct-1 [13].
• Analyzing the GLI complex and comparing it with Zif268 offers new perspectives on Zn finger-DNA recognition [14].
• In transient transfection assays, the WT1 protein functioned as a repressor of transcription when bound to the EGR-1 site [15].
• The binding sites obtained were similar to the sequence recognized by the early growth response-1 (EGR-1) gene product, a zinc finger-containing protein that is induced by mitogenic stimuli [16].

Chemical compound and disease context of EGR1

• Enhanced EGR1 activity promotes the growth of prostate cancer cells in an androgen-depleted environment [17].
• ATF3 and EGR-1 may provide a novel explanation for the antitumorigenic properties of LY294002 in human colorectal cancer cells [18].
• Activation of serine/threonine protein kinases and early growth response 1 gene expression by tumor necrosis factor in human myeloid leukemia cells [19].
• Results of kinase inhibitor studies also demonstrated that activation of Egr-1/NAG-1 by methylene-substituted diindolylmethanes (C-DIMs) was phosphatidylinositol 3-kinase-dependent, and this represents a novel receptor-independent pathway for C-DIM-induced growth inhibition and apoptosis in colon cancer cells [20].
• CONCLUSION: Glucose induces proinflammatory changes, including increases in AP-1, Egr-1, MMPs, and TF, the factors that regulate processes that are potentially relevant to atherosclerotic plaque rupture and thrombosis [21].

Biological context of EGR1

• This zinc-finger region, which is thought to bind DNA in a sequence-specific manner, is similar (greater than 80% on the amino acid level) to two previously described transcription factors pAT 225/EGR1 and pAT 591/EGR2 [22].
• We report that WT1, but not EGR1, can bind specific Igf-2 exonic RNA sequences, and that the zinc fingers are required for this interaction [23].
• WT1 encodes a transcription factor which binds to the EGR1 consensus sequence, mediating transcriptional repression [24].
• By hybridizing probes to metaphase cells with overlapping deletions involving 5q31, we have narrowed the critical region to a small segment of 5q31 containing the EGR1 gene [6].
• Transactivation of the EGR1 gene contributes to mutant p53 gain of function [25].

Anatomical context of EGR1

• In human histiocytic U937 cells mRNA of clone pAT 133 was constitutively expressed, whereas mRNA of pAT 225/EGR1 was induced upon induction of terminal differentiation [22].
• Electrophoretic mobility shift assay, with specific antibodies, showed that DB1 constitutively binds to this region whereas EGR1 binds in a T-cell activation-dependent manner [26].
• Transfection of EGR1 siRNA with T24 bladder cancer cell line significantly downregulated heparanase expression compared to the control siRNA transfection [27].
• Infection of a myoblast cell line with EGR1 and EGR1* adenovirus induced the endogenous gene for platelet-derived growth factor A chain (PDGF-A) [28].
• The results of nuclear run-on assays demonstrate that EGR-1 mRNA levels are increased in part by transcriptional activation of this gene in M-CSF-stimulated monocytes [29].

Associations of EGR1 with chemical compounds

• The minor groove binder chromomycin A3 inhibited EGR1 complex formation but resulted in a smaller increase of the TBP complex [8].
• Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression [29].
• Preincubation with cycloheximide was associated with superinduction of JUN and EGR1 in x-irradiated cells [30].
• Inhibition of protein kinase C activity by prolonged stimulation with phorbol 12-myristate 13-acetate or the protein kinase inhibitor H7 prior to irradiation attenuated the increase in EGR1 and JUN transcripts [30].
• The most abundant splicing variants contain a nine-nucleotide insertion encoding lysine, threonine, and serine (KTS) in the H-C link region between the third and fourth WT1 zinc fingers which disrupts binding to a previously defined WT1-EGR1 binding site [31].
• These data suggest that bombesin enhances Egr-1 expression leading to increased hPar1 transcription, thereby increasing PAR1 expression and function [32].

Physical interactions of EGR1

• We hypothesize that CpG hypomethylation in the heparanase promoter coupled with up-regulation of EGR1 levels may induce heparanase expression in human prostate cancer [33].
• Reporter constructs bearing the EGR-1 binding segment of the TGF-beta 1 promoter was activated 4- to 6-fold relative to a control reporter in either HT-1080 cells that stably expressed or parental cells cotransfected with an EGR-1 expression vector [34].
• EGR-1 binds to the ATF3 promoter as assessed by gel shift assay [18].
• Our findings suggest that high levels of EGR1 coupled with low levels of NAB2 can result in high, unrestrained EGR1 transcriptional activity in human prostate cancers [35].
• Egr-1 binding to a recognition sequence in the TIMP-1 promoter was demonstrated in gel retardation and reporter gene assays [36].

Enzymatic interactions of EGR1

• Therefore, it appears that the proximal CRE site is critical and the binding with CREB phosphorylated on Ser(133) is necessary for induction of the EGR-1 transcription by exendin-4 [37].
• Early growth response gene 1 (EGR1) is deleted in estrogen receptor-negative human breast carcinoma [38].

Regulatory relationships of EGR1

• Furthermore, Western blot and immunocytochemical analyses showed that constitutive overexpression of EGR1 promotes the translocation of AR from the cytoplasm to the nucleus [7].
• Our results show that Egr-1 is induced dramatically by TGZ but not by other PPAR gamma ligands [39].
• Amyloid peptide-induced cytokine and chemokine expression in THP-1 monocytes is blocked by small inhibitory RNA duplexes for early growth response-1 messenger RNA [40].
• Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression [41].
• EGR1 induction by various types of stress is markedly augmented in cells expressing mutant p53 [25].
• These results showed for the first time that Egr-1 regulates NDRG1 transcription through an overlapping Egr-1/Sp1 binding site that acts as a major site of positive regulation of the NDRG1 promoter by hypoxia signaling [42].

Other interactions of EGR1

• In the absence of p53, WT1 acts as a potent transcriptional activator of the early growth response gene 1 (EGR1) site, rather than a transcriptional repressor [24].
• Early growth response gene 1 modulates androgen receptor signaling in prostate carcinoma cells [7].
• Our results suggest that Egr-1 induction is a unique property of TGZ compared with other PPAR gamma ligands and is independent of PPAR gamma activation [39].
• The blocking of egr-1 with an antisense sequence prevented H. pylori-induced Egr-1 and CD44 protein expression [43].
• In NG108-15 cells, dbcAMP excerted a strong enhancing activity on the transactivation properties of NGFI-C while this was not observed when cells were transfected with NGFI-A [44].
• We provide novel evidence for a complex c-Jun-mediated mechanism that is essential for inducible EGR-1 expression [45].

Analytical, diagnostic and therapeutic context of EGR1

• Moreover, chromatin immunoprecipitation analysis indicates that mutant p53 is physically associated with the EGR1 promoter [25].
• Increased EGR1 protein expression was confirmed by Western blot analysis [46].
• We performed methylation-specific PCR targeting the CpG sites within the core-binding consensus motifs of EGR1 (GGCG) and Sp1 (GGGCGG) [27].
• We propose that gene therapy involving sustained EGR-1 expression may constitute a novel therapeutic principle in the treatment of cancer due to the simultaneous induction of multiple pathways of antiangiogenesis, growth arrest, and apoptosis induction in proliferating cells leading to preferential inhibition of angiogenesis and tumor growth [47].
• Egr-1 expression was assayed by immunoblotting and electrophoretic mobility shift assays using H. pylori-stimulated AGS cells [43].

References