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EGR1

Official Full Name
early growth response 1
Organism
Homo sapiens
GeneID
1958
Background
The protein encoded by this gene belongs to the EGR family of C2H2-type zinc-finger proteins. It is a nuclear protein and functions as a transcriptional regulator. The products of target genes it activates are required for differentitation and mitogenesis. Studies suggest this is a cancer suppressor gene. [provided by RefSeq, Dec 2014]
Synonyms
TIS8; AT225; G0S30; NGFI-A; ZIF268; ZNF225; KROX-24; ZIF-268;
Bio Chemical Class
mRNA target
Protein Sequence
MAAAKAEMQLMSPLQISDPFGSFPHSPTMDNYPKLEEMMLLSNGAPQFLGAAGAPEGSGSNSSSSSSGGGGGGGGGSNSSSSSSTFNPQADTGEQPYEHLTAESFPDISLNNEKVLVETSYPSQTTRLPPITYTGRFSLEPAPNSGNTLWPEPLFSLVSGLVSMTNPPASSSSAPSPAASSASASQSPPLSCAVPSNDSSPIYSAAPTFPTPNTDIFPEPQSQAFPGSAGTALQYPPPAYPAAKGGFQVPMIPDYLFPQQQGDLGLGTPDQKPFQGLESRTQQPSLTPLSTIKAFATQSGSQDLKALNTSYQSQLIKPSRMRKYPNRPSKTPPHERPYACPVESCDRRFSRSDELTRHIRIHTGQKPFQCRICMRNFSRSDHLTTHIRTHTGEKPFACDICGRKFARSDERKRHTKIHLRQKDKKADKSVVASSATSSLSSYPSPVATSYPSPVTTSYPSPATTSYPSPVPTSFSSPGSSTYPSPVHSGFPSPSVATTYSSVPPAFPAQVSSFPSSAVTNSFSASTGLSDMTATFSPRTIEIC
Open
Disease
Pain
Approved Drug
0
Clinical Trial Drug
2 +
Discontinued Drug
0

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Detailed Information

The EGR1 gene (Early Growth Response 1) belongs to the C2H2-type zinc finger protein family, primarily encoding a nuclear protein that functions as a transcriptional regulator involved in controlling gene expression. EGR1 is a significant transcription factor, playing crucial roles in various biological processes. One important transcription factor with important functions in many biological processes is EGR1. By binding to particular DNA sequences (EGR sites), it controls the transcription of target genes; these target genes are intimately linked to biological events including cell differentiation, proliferation, and tumor suppression. Cellular response, proliferation, differentiation, and gene damage repair all depend on EGR1 in some sense. Studies show that although in some tumor types, EGR1 acts as a tumor suppressor gene, in other malignancies its expression may show oncogenic features.

Structure and Function of EGR1

The structure of EGR1 is composed of several functional domains. Its N-terminus contains a strong activation domain followed by a repressive domain and a DNA-binding domain with three Cys2-His2-type zinc finger structures. The zinc finger structures are key for EGR1's binding to the DNA of its target genes, enabling the specific recognition and binding to the DNA sequence 5'-GCG(T/G)GGGCG-3' (EGR site) to initiate or inhibit the transcription of target genes. EGR1 further expands its range of regulatory target genes by interacting with other transcription factors such as c/EBPβ, Fos, and Jun.

EGR1 and Its Relationship with Tumors

Acting as a tumor suppressor gene in some tumors and perhaps encouraging tumor development and progression in others, EGR1 has multiple functions in many types of malignancies. Research on several genes linked to tumor suppression—including TGFβ, PTEN, and p53—has shown that EGR1 can control them. In glioma and melanoma, for example, EGR1 reduces tumor formation by inducing p21Waf1/Cip1-mediated death of tumor cells, hence activating tumor suppressor genes. In prostate cancer and stomach cancer, however, higher EGR1 expression is linked to malignant development.

Role of EGR1 in Physiological Functions

Particularly in the neurological system, EGR1 is important for numerous physiological processes. It is vital in neural activity and is expressed in several brain areas including the medial prefrontal cortex, striatum, hippocampal region, and amygdala. Higher activities like memory and learning as well as synaptic plasticity and neurotransmission are under control by EGR1. Long-term potentiation (LTP), whose maintenance depends on EGR1, is found to be essential for memory formation and reorganization and has major consequences. Variations in EGR1 expression patterns are intimately related to several neuropsychiatric diseases including schizophrenia.

EGR1 and Ischemia and Inflammatory Response

EGR1 also plays an important role in physiological and pathological processes like ischemia and inflammatory response. Through control of cytokine expression including IL1B and CXCL2, it helps in post-ischemic inflammatory response and tissue injury. Furthermore, EGR1 has distinct regulating roles in diseases including cardiovascular disease, acute lung injury, allergic dermatitis, and sepsis; loss of EGR1 control could therefore contribute to disease aggravation.

Regulatory Mechanisms of EGR1

EGR1's function is influenced by various upstream regulatory factors. Multiple transcription factor binding sites including cAMP response element (CRE), activator protein 1 (AP-1), EGR binding site (EBS), specificity protein 1 (Sp1), and nuclear factor κB (NF-κB) binding site abound in its promoter region. By attaching to its promoter, these regulating elements change the expression levels of EGR1. Elk-1, for instance, is a bidirectional regulator of EGR1 that either recruits histone acetyltransferases (such as p300/CBP) or inhibits EGR1 transcription by recruiting histone deacetylases (like mSin3A-HDAC).

Figure 1 illustrates the upstream regulators of EGR1 and depicts various regulatory elements of the EGR1 promoter, including hypoxic response element (HIF), cAMP response elements (CRE), EGR1 binding sites (EBS), specificity protein 1 (Sp1) elements, and serum response elements (SREs), along with transcription factors like HIF, CREB, cJun, EGR1, Sp1, NF-κB/p65, Elk, and SRF that bind to these elements to regulate EGR1 expression.Figure 1. Upstream regulators of EGR1. (Woodson CM, et al., 2022)

Downstream Target Genes of EGR1

As a transcription factor, EGR1 can regulate the expression of numerous target genes. Research from the ENCODE project indicates that approximately 54% of gene promoter regions contain EGR1 binding sites, highlighting EGR1's involvement in regulating extensive biological functions in various cell types. Genome-wide screening reveals that EGR1-regulated target genes are involved in pathways such as growth factor signaling, cell signal transduction, and protein synthesis, covering domains from chromatin to the cell membrane, further validating its significance in cellular functions.

EGR1 and Viral Infection

With EGR1 involved in these intricate and dynamic host-pathogen interactions set off by viral infection, they are by altering interferon signaling pathways, thereby disturbing cell cycle control, and so avoiding host immune responses, viruses sometimes dodge their targets. As a host cell transcription factor, EGR1 might be involved in the response of the host against viral invasion by controlling the expression of particular genes, therefore affecting the immunological reaction of the host cell. Though the exact function of EGR1 in viral infections is unknown, it might function as part of immunological control and therefore help the host to defend itself against viruses.

Transcriptional Regulatory Characteristics of EGR1

The transcriptional regulatory function of EGR1 is closely related to its structure. Its C-terminus contains a weak activation domain, while the N-terminus has a strong activation domain, enabling EGR1 to exhibit different transcriptional activities in various cell types. EGR1's function is influenced not only by transcription factor binding but also by various post-transcriptional modifications. For instance, the phosphorylation of EGR1 can alter its transcriptional activity, with modifications at certain phosphorylation sites enhancing EGR1's transcriptional activity while others may inhibit its function. Additionally, EGR1 can further expand its regulatory network by interacting with other transcription factors, affecting multiple biological processes within the cell.

References:

  1. Wang B, Guo H, et al. The Role of the Transcription Factor EGR1 in Cancer. Front Oncol. 2021 Mar 24;11:642547.
  2. Havis E, Duprez D. EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues. Int J Mol Sci. 2020 Feb 28;21(5):1664.
  3. Woodson CM, Kehn-Hall K. Examining the role of EGR1 during viral infections. Front Microbiol. 2022 Oct 21;13:1020220.
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