Alternative titles; symbols
HGNC Approved Gene Symbol: EGR1
Cytogenetic location: 5q31.2 Genomic coordinates (GRCh38): 5:138,465,479-138,469,303 (from NCBI)
EGR1 is an early growth response gene that displays FOS (164810)-like induction kinetics in fibroblasts, epithelial cells, and lymphocytes, following mitogenic stimulation (summary by Sukhatme et al., 1988).
EGR1 was first identified as a putative G0/G1 switch regulatory gene in human blood lymphocyte cultures and named G0S30 (Forsdyke, 1985). Sequence analysis of the murine gene predicted a protein with 3 DNA-binding zinc fingers (Sukhatme et al., 1988). According to work cited by Chavrier et al. (1989), EGR1 is also known as KROX24. EGR1 is also known as nerve growth factor-induced clone A (NGFIA).
Liu et al. (1996) observed that the EGR1 gene product directly controls transforming growth factor-beta-1 (TGFB1; 190180) gene expression, and they found that EGR1-dependent expression of TGFB1 inhibited human cancer cell growth in model cells. Huang et al. (1997) found that a variety of human tumor lines expressed little or no EGR1, in contrast to their normal counterparts. Liu et al. (1998) reviewed the role of EGR1 in suppression of growth and transformation and in induction of apoptosis. De Belle et al. (1999) reported that EGR1 and p53 (191170) additively suppressed transformed growth in a human fibrosarcoma cell line, but that EGR1 counteracted p53-dependent apoptosis. Liu et al. (1999) found that the growth regulatory properties of EGR1 involve coordinated regulation of TGFB1 and fibronectin (FN1; 135600) by direct binding and stimulation of the TGFB1 and FN1 promoters. The resulting protein products are secreted and lead to increased expression of plasminogen activator inhibitor-1 (PAI1; 173360) via TGFB1. Secreted FN1 and PAI1 function to enhance cell attachment and normal cell growth.
DNAzymes (DNA-based enzymes) are cation-dependent enzymatic molecules composed entirely of DNA that can be engineered to cleave target mRNA in a gene-specific and catalytically efficient manner. To study EGR1 function, Fahmy et al. (2003) used DNAzymes to target a specific motif in the 5-prime untranslated region of EGR1 mRNA and found that they inhibited EGR1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr1-deficient animals, and inhibited growth of a human breast cancer carcinoma cell line in nude mice. Egr1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation, or other hematologic parameters. Fahmy et al. (2003) found that these agents inhibited endothelial expression of FGF2 (134920), a proangiogenic factor downstream of EGR1, but not of VEGF (192240). Egr1 DNAzymes also repressed neovascularization of rat cornea. Thus, Fahmy et al. (2003) concluded that microvascular endothelial cell growth, neovascularization, tumor angiogenesis, and tumor growth are processes that are critically dependent on EGR1.
Bozon et al. (2003) explored whether ZIF268, an activity-dependent inducible immediate early gene required for consolidation of new memories, is also recruited for reconsolidation of recognition memory following reactivation. They showed that when a consolidated memory for objects was recalled, Zif268 mutant mice were impaired in further long-term but not short-term recognition memory. The impairment was specific to reactivation with the previously memorized objects in the relevant context, occurred in delayed recall, and did not recover over several days. Bozon et al. (2003) concluded that their findings indicated that immediate early gene-mediated transcriptional regulation in neurons is one common molecular mechanism for the storage of newly formed and reactivated recognition memories.
By infusing antisense oligodeoxynucleotides into the hippocampus of rats, Lee et al. (2004) showed that consolidation and reconsolidation are doubly dissociable component processes of memory. Consolidation involves brain-derived neurotrophic factor (BDNF; 113505) but not the transcription factor ZIF268, whereas reconsolidation recruits ZIF268 but not BDNF. Lee et al. (2004) concluded that their findings confirmed a requirement for BDNF specifically in memory consolidation and also resolved the role of ZIF268 in brain plasticity, learning, and memory.
By Affymetrix microarray, real-time PCR, immunoblot, and chromatin immunoprecipitation assays, Virolle et al. (2003) found that mouse Egr1 was involved in the proliferation and survival of prostate cancer cells by regulating several target genes, including cyclin D2 (CCND2; 123833), p19(Ink4d) (600927), and Fas (134637). They also showed that EGR1 was responsible for overexpression of CCND2 in a tumorigenic human prostate cell line. One mechanism used by Egr1 to confer resistance to apoptotic signals was the ability of Egr1 to inhibit Fas expression, leading to insensitivity to FasL (134638).
Revest et al. (2005) found that the effects of stress-related glucocorticoid receptor (138040) signaling in mouse hippocampus were mediated by the MAPK pathway and Egr1 upregulation.
Sukhatme et al. (1988) assigned the EGR1 gene to chromosome 5q23-q31 by a combination of somatic cell and in situ hybridization. Localization of the human gene to chromosome 5 had been confirmed by other workers, and the location of the mouse gene has been found to be chromosome 18. Although the EGR1 and EGR2 genes encode almost identical zinc fingers (Lemaire et al., 1988), they are not closely situated in either genome.
Loss of chromosome 5q is observed in 10 to 15% of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; 601626) and in 40% of patients with therapy-related MDS or AML. In addition, patients with 5q deletion syndrome (153550) show hematologic abnormalities, including refractory anemia and abnormal megakaryocytes (Le Beau et al., 1993; Joslin et al., 2007). By cytogenetic analysis and hybridization techniques, Le Beau et al. (1993) identified a common 2.8-Mb critical region containing the EGR1 gene on 5q31 that was deleted in 135 patients with hematologic abnormalities and 5q deletions, including 85 patients with de novo MDS or AML, 33 with therapy-related MDS or AML, and 17 with MDS and the 5q deletion syndrome. Le Beau et al. (1993) postulated that EGR1 or another closely-linked gene may act as a tumor suppressor gene.
Lee et al. (1996) studied transgenic mice in whom the Egr1 gene had been inactivated and found female infertility secondary to deficiency of luteinizing hormone-beta (152780). Ovariectomy led to increased amounts of follicle stimulating hormone-beta (136530) but not LH-beta mRNA, which suggested a pituitary defect. A conserved, canonical NGFIA site in the LHB promoter was required for synergistic activation by NGFIA and steroidogenic factor-1 (SF1; 184757). The authors concluded that NGFIA apparently influences female reproductive capacity through its regulation of LH-beta transcription.
Das et al. (2001) used primary mouse embryonic fibroblast cells from Egr1 -/- and Egr1 +/- mice to examine the interactive role of EGR1 with p53 during apoptosis. They observed enhanced apoptosis associated with elevated levels of p53 after ionizing radiation in the Egr1 +/- cells, whereas p53 was downregulated in the Egr -/- cells, as measured by TUNEL and reporter gene analysis. RB1 (614041), an EGR1 target gene, forms a trimeric complex with MDM2 (164785) to prevent MDM2-mediated p53 degradation. Western blot analysis showed low levels of Rb in Egr1 -/- cells compared with Egr +/- cells before and after radiation. Immunoblot analysis also showed elevated Mdm2-p53 and low amounts of Rb-Mdm2 in the Egr1 -/- cells after radiation. Das et al. (2001) concluded that apoptosis requires intact EGR1 as well as p53 and that the proapoptotic function of EGR1 involves the mediation of RB.
Ayadi et al. (2001) determined that Elk3 (600247) negatively regulates Egr1 expression during mouse development and specifically binds SRE5 of the Egr1 promoter. Mice expressing a mutant form of Elk3 that was unable to bind DNA expressed elevated levels of Egr1 in heart and pulmonary arteries at embryonic day 18.5. Elevated Egr1 expression was associated with vascular defects, particularly dilated lymphatic arteries. Mutant mice died after birth from respiratory failure resulting from the accumulation of chyle in the thoracic cage. Ayadi et al. (2001) hypothesized that Erg1 dysfunction could be responsible for obstructions that ultimately affect the lymphatics.
Jones et al. (2001) generated mice deficient in Zif268 to determine whether it is required for the maintenance of late long-term potentiation and for the expression of long-term memory. They showed that whereas mutant mice exhibited early long-term potentiation in the dentate gyrus, late long-term potentiation was absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and nonspatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Jones et al. (2001) concluded that ZIF268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories.
Frankland et al. (2004) presented neuroanatomic, pharmacologic, and genetic results demonstrating that the anterior cingulate cortex plays a critical role in remote memory for contextual fear conditioning. Imaging of activity-dependent genes showed that the anterior cingulate is activated by remote memory and that this activation is impaired by a null alpha-calmodulin kinase II (CAMK2A; 114078) mutation that blocks remote memory. Accordingly, reversible inactivation of this structure in normal mice disrupts remote memory without affecting recent memory. Frankland et al. (2004) found that Zif268 expression was elevated in wildtype but not alpha-calmodulin kinase II heterozygote mice, after the remote memory test in the anterior cingulate cortex.
By partial hepatectomy of Egr1 null mice, Liao et al. (2004) examined the role of Erg1 in liver regeneration. Egr1 deficiency was associated with an impaired hepatic regenerative response that was characterized by delayed hepatocellular progression through the mitotic spindle assembly checkpoint. Impaired regeneration was also associated with increased activation of p38 MAPK (600289) and reduced induction of Cdc20 (603618).
Experiments in chickens have implicated Egr1 in the feedback mechanisms for visual control of axial eye growth and myopia development (Fischer et al., 1999). Schippert et al. (2007) evaluated whether an Egr1 knockout mouse had longer and more myopic eyes than did Egr1 heterozygotes and Egr1 wildtype mice with near-identical genetic backgrounds. The Egr1 knockout mice had longer eyes and a relative myopic shift in refraction, with additional minor effects on anterior chamber depth and corneal radius of curvature. Paraxial schematic eye modeling suggested changes in the optics of the crystalline lens as well. With increasing age, the differences between mutant and wildtype mice declined, although the differences in refraction persisted over the observation period (P28-P98). Grating acuity was not affected by the lack of the Egr1 protein during development.
Joslin et al. (2007) found that Egr1 -/- and Egr1 +/- mice had normal hematopoietic potential under physiologic conditions. However, in response to N-ethyl-nitrosourea, these mutant mice developed immature T-cell lymphomas or myeloproliferative disorders (MPD) at increased rates and with shorter latencies compared to wildtype mice. The MPD phenotype was characterized by increased white blood cell counts, anemia, and thrombocytopenia, with ineffective erythropoiesis in bone marrow and spleen, recapitulating some of the features of human MDS and AML with 5q deletions. No biallelic Egr1 mutations were found in malignant cells of Egr +/- mice, and Egr1 -/- and Egr1 +/- mice developed the disorders at a similar frequency, suggesting that loss of a single allele of Egr1 is sufficient for disease progression in cooperation with secondary mutations. The findings indicated that Egr1 acts as a tumor suppressor gene.
Ayadi, A., Zheng, H., Sobieszczuk, P., Buchwalter, G., Moerman, P., Alitalo, K., Wasylyk, B. Net-targeted mutant mice develop a vascular phenotype and up-regulate egr-1. EMBO J. 20: 5139-5152, 2001. [PubMed: 11566878] [Full Text: https://doi.org/10.1093/emboj/20.18.5139]
Bozon, B., Davis, S., Laroche, S. A requirement for the immediate early gene zif268 in reconsolidation of recognition memory after retrieval. Neuron 40: 695-701, 2003. [PubMed: 14622575] [Full Text: https://doi.org/10.1016/s0896-6273(03)00674-3]
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Das, A., Chendil, D., Dey, S., Mohiuddin, M., Mohiuddin, M., Milbrandt, J., Rangnekar, V. M., Ahmed, M. M. Ionizing radiation down-regulates p53 protein in primary Egr-1(-/-) mouse embryonic fibroblast cells causing enhanced resistance to apoptosis. J. Biol. Chem. 276: 3279-3286, 2001. [PubMed: 11035041] [Full Text: https://doi.org/10.1074/jbc.M008454200]
de Belle, I., Huang, R.-P., Fan, Y., Liu, C., Mercola, D., Adamson, E. D. p53 and Egr-1 additively suppress transformed growth in HT1080 cells but Egr-1 counteracts p53-dependent apoptosis. Oncogene 18: 3633-3642, 1999. [PubMed: 10380885] [Full Text: https://doi.org/10.1038/sj.onc.1202696]
Fahmy, R. G., Dass, C. R., Sun, L.-Q., Chesterman, C. N., Khachigian, L. M. Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nature Med. 9: 1026-1032, 2003. [PubMed: 12872165] [Full Text: https://doi.org/10.1038/nm905]
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Huang, R.-P., Fan, Y., de Belle, I., Niemeyer, C., Gottardis, M. M., Mercola, D., Adamson, E. D. Decreased Egr-1 expression in human, mouse and rat mammary cells and tissues correlates with tumor formation. Int. J. Cancer 72: 102-109, 1997. [PubMed: 9212230] [Full Text: https://doi.org/10.1002/(sici)1097-0215(19970703)72:1<102::aid-ijc15>3.0.co;2-l]
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Lemaire, P., Revelant, O., Bravo, R., Charnay, P. Two genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells. Proc. Nat. Acad. Sci. 85: 4691-4695, 1988. [PubMed: 3133658] [Full Text: https://doi.org/10.1073/pnas.85.13.4691]
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Liu, C., Adamson, E., Mercola, D. Transcription factor EGR-1 suppresses the growth and transformation of human HT-1080 fibrosarcoma cells by induction of transforming growth factor beta-1. Proc. Nat. Acad. Sci. 93: 11831-11836, 1996. [PubMed: 8876223] [Full Text: https://doi.org/10.1073/pnas.93.21.11831]
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Sukhatme, V. P., Cao, X., Chang, L. C., Tsai-Morris, C.-H., Stamenkovich, D., Ferreira, P. C. P., Cohen, D. R., Edwards, S. A., Shows, T. B., Curran, T., Le Beau, M. M., Adamson, E. D. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell 53: 37-43, 1988. [PubMed: 3127059] [Full Text: https://doi.org/10.1016/0092-8674(88)90485-0]
Virolle, T., Krones-Herzig, A., Baron, V., De Gregorio, G., Adamson, E. D., Mercola, D. Erg1 promotes growth and survival of prostate cancer cells: identification of novel Egr1 target genes. J. Biol. Chem. 278: 11802-11810, 2003. [PubMed: 12556466] [Full Text: https://doi.org/10.1074/jbc.M210279200]