EGR is an early growth response gene that displays FOS-like induction kinetics in fibroblasts, epithelial cells, and
lymphocytes, following mitogenic stimulation. It 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. The zinc finger transcription factor Krox-24 (NGFI-A, Egr-1) is encoded by an immediate-early
serum response gene expressed in various physiological situations and tissues.
This gene was found to be regulated by gonadotropins in DNA arrays.
NCBI Summary:
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]
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
Maternal Obesity is Associated with Ovarian Inflammation and Up-regulation of Early Growth Response Factor (Egr)-1. Ruebel M et al. (2016) Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a pro-inflammatory gene signature and up-regulation of Egr-1 protein in ovaries from obese (OB, n=7) compared to lean (LN, n=10) female Sprague Dawley rats during the peri-implantation period at 4.5 days post-coitus (dpc). Obesity was induced by overfeeding (40% excess calories for 28 d) via total enteral nutrition prior to mating. OB dams had higher body weight (p<0.001), greater fat mass (p<0.001), reduced lean mass (p<0.05), and developed metabolic dysfunction with elevated serum lipids, insulin, leptin, and CCL2 (p<0.05) compared to LN dams. Microarray analyses identified 284 differentially-expressed genes between ovaries from LN vs. OB dams (±1.3 fold, p<0.05). RT-qPCR confirmed a decrease in expression of glucose transporters GLUT4 and GLUT9 and elevation of pro-inflammatory genes including CCL2, CXCL10, CXCL11, CCR2, CXCR1, and TNF-α in ovaries from OB compared to LN (p<0.05). Protein levels of PI3K and phosphorylated AKT were significantly decreased (p<0.05) while nuclear levels of Egr-1 (p<0.05) were increased in OB compared to LN ovaries. Moreover, Egr-1 was localized to granulosa cells, with highest expression in cumulus cells of pre-ovulatory follicles. mRNA expression of VCAN, AURKB and PLAT (p<0.05) correlated with %visceral fat weight (r=0.51, -0.77, and -0.57, p<0.05, respectively), suggesting alterations in ovarian function with obesity. In summary, maternal obesity led to an up-regulation of inflammatory genes and Egr-1 expression in peri-implantation ovarian tissue, and a concurrent down-regulation of GLUTs and AKT and PI3K protein levels.//////////////////
Cellular localization
Nuclear
Comment
Ovarian function
Ovulation, Luteinization
Comment
Lawrence L. Espey et al 2000 reported the induction of Early Growth Response Protein-1 (EGR-1) Gene Expression in the Rat Ovary
in Response to an Ovulatory Dose of Human Chorionic Gonadotropin.
Immature Wistar rats were primed
with 10 IU equine CG (eCG), sc, and 48 h later the 12-h ovulatory process was initiated by 10 IU hCG, sc. Ovarian RNA
was extracted at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the primed animals were injected with hCG. The RNA extracts were
used for RT-PCR differential display for random detection of gene expression in the stimulated ovarian tissue. In situ hybridization indicated that the Egr-1 messenger RNA was in the
granulosa layer of mature follicles. Western blotting confirmed the temporal pattern of Egr-1 expression detected by
differential display, Northern analysis and in situ hybridization.
Expression regulated by
LH, Growth Factors/ cytokines
Comment
Regulation and action of Early Growth Response 1 in bovine granulosa cells. Han P et al. (2017) Fibroblast growth factors (FGF) modify cell proliferation and differentiation through receptor tyrosine kinases, which stimulate the expression of transcription factors including members of the early growth response (EGR) family. In ovarian granulosa cells, most FGFs activate typical response genes, although the role of EGR proteins has not been described. In the present study, we determined the regulation of EGR mRNA by FGFs and explored the role of EGR1 in the regulation of FGF response genes. Addition of FGF1, FGF2, FGF4 or FGF8b increased EGR1 and EGR3 mRNA levels, whereas FGF18 increased only EGR1 mRNA abundance. No mRNA encoding EGR2 or EGR4 was detected. Overexpression of EGR1 increased mRNA encoding EGR3 and the FGF response genes SPRY2, NR4A1, FOSL1 and others, and also increased phosphorylation of MAPK3/1. The increase in MAPK3/1 activity likely contributed to the EGR1-mediated increase in NR4A1, FOSL1 and EGR3, as suggested by the use of the MAPK inhibitor PD98059. Knock-down of EGR3 did not alter the ability of FGF8b to stimulate SPRY2 mRNA levels. These data demonstrate regulation of EGR1 and EGR3 mRNA abundance by FGFs in granulosa cells, and that EGR1 is likely an upstream component of FGF signaling in granulosa cells.//////////////////
Characterization of bovine early growth response factor-1 and its gonadotropin-dependent regulation in ovarian follicles prior to ovulation. Sayasith K et al. Early growth response factor-1 (EGR-1) is a transcription factor that is involved in the transactivation of several genes. The objective of this study was to characterize gonadotropin-dependent regulation of bovine EGR-1 in preovulatory follicles prior to ovulation. Bovine EGR-1 cDNA was obtained by RT-PCR, 5'- and 3'-RACE, its open reading frame composed of 1623 bp, and its coding region encodes a 540-amino acid protein that displays 62-93% identity to known mammalian homologs. The regulation of EGR-1 mRNA was studied in bovine preovulatory follicles which were isolated 0-24 h post-hCG using semiquantitative RT-PCR/Southern blot. Results revealed that the levels of EGR-1 mRNA were very low in follicles at 0 h, markedly increased at 6 h (P < 0.05) when compared to 0 h, and decreased between 12 and 24 h post-hCG. High levels of the EGR-1 mRNA were also observed in corpus luteum, uterus, kidney, pituitary, and spleen, moderate and low in other bovine tissues tested. Analyses performed on isolated preparations of granulosa and theca cells indicated that EGR-1 mRNA was regulated in both cell types, with a predominant expression in granulosa cells. Immunohistochemistry on sections of preovulatory follicles isolated before and after hCG confirmed its protein expression in granulosa cells, 24 h post-hCG. Studies of EGR-1 regulation in primary granulosa cells cultured with forskolin showed that levels of EGR-1 mRNA were low at 0 h, highly increased at 6 h post-forskolin (P < 0.05), and declined to steady state thereafter. Immunoblotting confirmed forskolin-induced EGR-1 protein in cultures. Interestingly, overexpression of EGR-1 increased the levels of mRNA for prostaglandin (PG) G/H synthase-2 (PGHS-2), PG E synthase (PGES), PG E2 receptor (EP2), LH receptor (LH-R), but not for cytochrome P450-side chain cleavage (P450scc), and cytochrome P450 aromatase (P450arom) in granulosa cultures. Thus, this study reports for the first time, a gonadotropin-dependent induction of follicular EGR-1 prior to ovulation in large monoovulatory species and its stimulating effect on the expression of genes known to be involved in prostaglandin biosynthesis pathway, thereby suggesting its potential involvement in the regulation of preovulatory events in cattle.
Ovarian localization
Granulosa, Luteal cells
Comment
Adenosine 5'-Triphosphate Activates Nuclear Translocation of Mitogen-Activated Protein Kinases Leading to the Induction of Early Growth Response 1 and Raf Expression in Human Granulosa-Luteal Cells.
Tai CJ, et al .
With the stimulation of many types of cell surface receptors, MAPKs are activated. We have previously demonstrated an effect of extracellular ATP on ERKs and gonadotropin- induced progesterone secretion, implicating the significance of ATP in the regulation of ovarian function. However, little is known about the specific role of ATP in the subsequent MAPK-induced signaling cascade in human granulosa-luteal cells (hGLCs). The present study was designed to examine the effect of ATP on the activation of the MAPK signaling pathway, including nuclear translocation and the expression of the immediate early genes in hGLCs. Western blot analysis, using a monoclonal antibody, which detected the total and phosphorylated forms of ERK1 and ERK2 (p42(mapk) and p44 (mapk), respectively), demonstrated that exogenous ATP evoked ERKs in a dose- and time-dependent manner. In contrast, p38 and JNK were not significantly activated after ATP treatment. To examine the translocation of activated ERKs, fluorescein isothiocyanate-conjugated secondary antibody was used to detect the distribution of total and phosphorylated ERKs. Immunofluorescent staining revealed that phosphorylated ERKs were translocated from cytoplasm into nucleus subsequent to 10 弮m ATP treatment. To study the gene(s) induced by exogenous ATP, mRNA was extracted from hGLCs in the presence or absence of 10 弮m ATP. Gene array for 23 genes associated with members of the mitogenic pathway cascade and immediate early genes revealed that the expression of early growth response 1 and c-raf-1 was increased. To our knowledge, this is the first demonstration of the ATP-induced nuclear translocation of MAPKs in the human ovary. These results suggest that the MAPK signaling pathway plays a role in mediating ATP actions in the human ovary.
Follicle stages
Preovulatory, Corpus luteum
Comment
Prostaglandin F2{alpha} (PGF2{alpha}) Stimulates the Expression and Secretion of TGFB1via Induction of the Early Growth Response 1 Gene (EGR1) in the Bovine Corpus Luteum. Hou X et al. In most mammals, prostaglandin F2alpha (PGF2alpha) is believed to be a trigger that induces the regression of the corpus luteum (CL), whereby progesterone synthesis is inhibited, the luteal structure involutes, and the reproductive cycle resumes. Studies have shown that the early growth response 1 (EGR1) protein can induce the expression of pro-apoptotic proteins, suggesting that EGR1 may play a role in luteal regression. Our hypothesis is that EGR1 mediates the actions of PGF2alpha by inducing the expression of transforming growth factor beta 1 (TGFB1), a key tissue remodeling protein. The levels of EGR1 mRNA and protein were up-regulated in the bovine CL during PGF2alpha-induced luteolysis in vivo and in PGF2alpha-treated luteal cells in vitro. Using chemical and genetic approaches, the RAF/MEK1/ERK pathway was identified as a proximal signaling event required for the induction of EGR1 in PGF2alpha-treated cells. Treatment with PGF2alpha increased the expression of TGFB1 mRNA and protein as well as the binding of EGR1 protein to TGFB1 promoter in bovine luteal cells. The effect of PGF2alpha on TGFB1 expression was mimicked by a PKC/RAF/MEK1/ERK activator or adenoviral-mediated expression of EGR1. The stimulatory effect of PGF2alpha on TGFB1 mRNA and TGFB1 protein secretion was inhibited by blockade of MEK1/ERK signaling and by adenoviral-mediated expression of NAB2, an EGR1 binding protein that inhibits EGR1 transcriptional activity. Treatment of luteal cells with TGFB1 reduced progesterone secretion, implicating TGFB1 in luteal regression. These studies demonstrate that PGF2alpha stimulates the expression of EGR1 and TGFB1 in the CL. We suggest that EGR1 plays a role in the expression of genes whose cognate proteins coordinate luteal regression.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:Lee et al 1996 reported luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A
(Egr-1).
Topilko P, et al 1998 reported multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)-targeted
mice. Mice homozygous for the EGR-1 mutation have a reduced body size,
and both males and females are sterile. These phenotypes were related to defects in the anterior
pituitary of both sexes and in the ovary. In the pituitary, two cell lineages expressing Krox-24 are
differentially affected by the mutation: somatotropes present abnormal cytological features and are
reduced in number, consistent with the decreased GH content observed in these animals; in contrast
gonadotropes are normal in number, but specifically fail to synthesize the beta-subunit of LH. In the
ovary, LH receptor expression is prevented, indicating an involvement of Krox-24 at two levels at
least of the pituitary-gonadal axis.