The gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.

Genomic size 3824 bp; 2 exons; + strand of chromosome 5.

mRNA size: 3132, ORF 271-1902 (1632 nt coding sequence).
Rare occurrence of splice variants (2 variants have been described in the brain).
The EGR1 promoter contains five SREs (serum response elements). Increased transcription in response to growth factors or stress is most commonly mediated by transcription factors of the Elk-1/SAP-1/SAP-2 family, which are activated by MAP-Kinase family (mitogen activated protein kinase). Elk-1 associates with CBP (CREB binding protein) and SRF (serum response factor) to form the Ternary Complex Factor, which binds to the SREs.
The promoter also contains several SP1 consensus sequences; a putative AP-1 binding site (not conserved); at least one functional CRE (cAMP regulatory element). EGR1 regulates its own transcription by binding to functional EBS (EGR1 binding sites). A functional NFkB (p65/RelA) binding site is contained in the EGR1 promoter that allows NF-kB to increase EGR1 transcription in response to UV (ultra-violet) irradiation. EGR1 is a target of ETS transcription factors that are involved in hematopoiesis, angiogenesis and neoplasia. Finally, EGR1 promoter contains two ATF5 (activating transcription factor 5) consensus sequences at a conserved promoter position and is induced by ATF5 in cancer cell lines.

The protein contains 543 amino acids. Its predicted molecular weight is 57.5 kDa, however the protein migrates at an apparent molecular weight of 75-85 kDa in SDS-PAGE. It has a very short half-life of ~30 minutes to 1 hour.
EGR1 contains a highly conserved DNA-binding domain composed of three Cys2-His2 type zinc-fingers that bind to the prototype target sequence GCG(G/T)GGGCG; a nuclear localization signal that requires amino acids 361-419 (zinc fingers 2 and 3) and amino acids 315-330; two activator domains; a repressor domain between amino acids 281-314. EGR1 binds to regulatory proteins called NAB-1 (NGFA-I binding protein) and NAB2 through its repressor domain.
Post-translational modifications include phosphorylation, acetylation, ubiquitination and sumoylation (figure 1).

Ubiquitous. Exhibits a distinct expression pattern in the brain. Constitutive protein expression is low in many tissues. EGR1 expression is very rapidly and strongly induced by growth factors and mitogens, cytokines, environmental and mechanical stresses, as well as DNA damage (hpr).

Nuclear. Occasional cytoplasmic localization observed in cancer cells.

EGR1 is an early response transcription factor with DNA binding activity that activates the transcription of several hundred genes. Depending on the cell type and the stimulus, EGR1 induces the expression of growth factors, growth factor receptors, extracellular matrix proteins, proteins involved in the regulation of cell growth or differentiation, and proteins involved in apoptosis, growth arrest, and stress responses.
EGR1 can compete with transcription factor SP1, which is involved in the constitutive expression of housekeeping genes and other regulatory genes. Because the consensus sequence for SP1 and EGR1 binding overlaps, EGR1 often displaces SP1 from gene promoters.
EGR1 transcriptional activity is inhibited by direct interaction with the proteins NAB1 and NAB2. Their expression is also inducible, albeit delayed compared to EGR1 induction. NAB1 and NAB2 impose an early negative feedback and thus ensure that EGR1 activity is transient, before the protein is degraded. It should be noted that deregulated expression of NAB proteins in disease may contribute to alteration of EGR1 function. For example, elevated expression of NAB2 in endothelial cells reduces angiogenesis, whereas loss of NAB2 in prostate cancer contributes to increased EGR1 activity.
EGR1 has various neurocognitive functions. It is involved in the regulation of neuronal activity and may control neuronal plasticity. EGR1 controls tissue repair, wound healing, liver regeneration, atherosclerosis, fibrosis, and other inflammation or stress-related responses. It is considered a key master regulator in cardiovascular pathology by promoting atherosclerosis, intimal thickening following vascular injury, ischemia, allograft rejection and cardiac hypertrophy. Finally, EGR1 regulates cell response to hypoxia, promotes the formation of new blood vessels from the pre-existing vasculature, and triggers tumor angiogenesis.
In cancer, EGR1 is traditionally considered a tumor suppressor. However, accumulating evidence now indicates that it can act both as a tumor suppressor and as a tumor promoter, depending on the context.
EGR1 protects normal cells from transformation by inducing apoptosis or growth arrest upon DNA damage. A strong evidence for EGR1 pro-apoptotic function is that EGR1^-/- mouse embryo fibroblasts are resistant to apoptosis induced by ionizing radiation. Although EGR1-deficient mice do not spontaneously develop tumors, they display accelerated tumor growth in a two-step carcinogenesis model of skin cancer. As an example, UV-B radiation of keratinocytes induces EGR1 expression through activation of NFkB (p65/RelA), which mediates apoptosis and acts as a protection mechanism against the tumorigenic effect of UV. These observations support the notion that EGR1 participates in the suppression of DNA damage-induced tumors.
EGR1 is involved in the chemopreventive or antiproliferative effect of natural compounds such as curcumin, genistein, isoflavone, green tea extracts, and others. It also mediates the anti-proliferative effects of NSAIDs (non-steroid anti-inflammatory drug) and of other chemotherapeutic agents such as cisplatin.
In many cancer cells, EGR1 is induced by radiation, chemotherapeutic drugs, steroids and anti-inflammatory drugs, and is required for the growth arrest or apoptotic effect of these treatments. Lack of EGR1 response confers chemoresistance. This may be exploited by restoring EGR1 expression through gene therapy to increase the efficacy of radiotherapy of chemotherapy.
At later stages of cancer EGR1 tumor suppressor function is impaired by the frequent inactivation, in human tumors, of two major tumor suppressor targets of EGR1 (namely PTEN and TP53). In addition, EGR1 induction by growth factors or stress is blocked in some types of cancer cells ("resistance" to induction). This has been described in fibrosarcoma, prostate cancer, colon cancer, and RAS-transformed cells. Several mechanisms are involved. For example, RAS-induced transformation of fibroblasts results in the aberrant constitutive activation of PI3-kinase (phosphatidyl inositol 3-kinase), which causes degradation of SRF and prevents Elk-1-mediated induction of EGR1. In colon cancer cells, it is the mutational activation of Wnt-1 that prevents the SRF-mediated induction of EGR1 and other early genes in response to mitogens. Alternatively, overexpression of phospholipase D in glioma cells attenuates mitogen-induced EGR1 expression through activation of PI3-kinase.
On the other hand, EGR1 overexpression in some cancer types directly promotes cancer progression and tumor growth by increasing the expression and secretion of growth factors and cytokines, extracellular matrix proteins (Barbolina et al., 2007; Shin et al., 2010) and proteases. Egr-1 mediates growth factor-induced downregulation of E-cadherin by inducing an E-cadherin transcription repressor, Snail or Slug, which contributes to tumor invasion (Grotegut et al., 2006; Cheng et al., 2013). Mechanisms that can cause EGR1 overexpression in tumor cells include p53 mutations (observed in gliomas and prostate cancer). Mutant p53 upregulates EGR1 in prostate cancer cells by activating ERK (extracellular regulated kinase) through undefined mechanism. Constitutive activation of the ERK pathway in tumor cells appears to be a consistent cause of EGR1 expression and is often due to genetic defects affecting upstream regulators of the ERK pathway. For example, a mutation of EGFR (epidermal growth factor receptor) commonly found in lung cancer cells causes EGR1 overexpression and activation through activation of the ERK pathway. Similarly, a mutation of B-RAF present in a high percentage of melanoma results in constitutive activation of ERK and up-regulation of EGR1.

Three other family members: EGR2, EGR3 and EGR4 (see figure 2).

Mutations in the EGR1 gene have not been found; altered expression level is the most common contributor to tumorigenesis.
Chromosome loss/deletions:
- The long arm of chromosome 5 in which EGR1 is located is consistently deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Loss of chromosome 5 or deletion in 5q is the most common karyotypic abnormality in MDS, occurring in 10% of new MDS/AML patients and in 40% of patients with therapy-related MDS or AML. Mice lacking at least one allele of EGR1 develop symptoms similar to that of MDS after they are exposed to a carcinogen (i.e. mono- or bi-allelic loss of EGR1 accelerates the development of pre-leukemic disorders).
- Loss of 5q is consistently associated with estrogen receptor-negative (ER^-) breast carcinoma and is seen in 86% of breast carcinomas carriers of BRCA1 (breast cancer 1) and BRCA2 mutations. Fluorescence in situ hybridization confirmed the association of EGR1 loss with ER^- breast carcinoma; loss of EGR1 correlated with high grade.
- In mouse model with a deletion of chromosome 5, loss of Tp53 activity in cooperation with EGR1 and adenomatous polyposis coli (APC) haploinsufficiency, accelerates the development of AML (Stoddart et al., 2013).