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Department of Biology, Trinity University (L.L.E., T.U., M.S., B.V.), San Antonio, Texas 78212; Department of Cell Biology, Baylor College of Medicine (D.L.R., R.L.R., J.S.R.), Houston, Texas 77030; and Department of Obstetrics and Gynecology, Kumamoto University School of Medicine (H.O.), Kumamoto, Japan 860-8556
Address all correspondence and requests for reprints to: Lawrence Espey, Ph.D., Department of Biology, Trinity University, San Antonio, Texas 78212. E-mail: lespey{at}trinity.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When extracellular ligands such as trophic hormones stimulate cytokinetic phenomena such as the ovulation/luteinization transformation, the target tissue response involves alterations in gene expression in the activated cells. The genomic response usually includes the induction of immediate-early transcription factor genes such as early growth response protein-1 (Egr-1; also known as Krox-24, NGFI-A, zif/268, cef5, and TIS8) gene, and/or the c-fos and c-jun genes (4, 5). Although rapid (albeit transient) Egr-1 gene induction is a common component of the response to mitogenic hormones that stimulate cells to undergo G0-G1 transition (5, 6), this transcription factor is also known to increase in cells that are only differentiating without dividing, such as LH-secreting cells in the pituitary (7). After it is translated, the Egr-1 protein translocates into the nucleus and functions as a zinc finger transcription factor to regulate the expression of an estimated 80–100 other genes, increasing their transcription rates as much as 100-fold (4, 5).
The present report characterizes, for the first time, ovarian expression of the Egr-1 gene during the early stages of the ovulatory process in the gonadotropin-primed immature rat. This predictable gene expression was discovered during differential display RT-PCR analysis of messenger RNAs (mRNAs) that are expressed in the ovary at the time of ovulation. The report describes the temporal and spatial patterns of expression of the gene during a periovulatory period ranging from 12 h before to 12 h after follicular rupture. It also assesses the effects of progesterone and PG synthesis on expression of the Egr-1 gene.
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Materials and Methods |
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Ovarian PGE2 and progesterone vs. ovulation
rate
Ovaries for PGE2 and progesterone RIAs
were extirpated at 8 h after hCG treatment, because at this time
rat ovaries synthesize maximal amounts of these two ovulation-related
agents (9). PGE2 was assayed as described
previously (9). Progesterone levels in aqueous extracts of homogenized
ovaries were assayed according to instructions in a commercial RIA kit
for this steroid (TKPG1, Diagnostic Products, Los Angeles,
CA). A reagent kit (P5656, Sigma, St. Louis, MO) was used
to perform protein assays on aliquots of each RIA sample. The amount of
eicosanoid or steroid per sample was expressed as nanograms per mg
protein in each sample. The ovulation rate in the experimental animals
was determined by a procedure that also has been described previously
(8). Ova were counted in the oviducts at 24 h after hCG
administration, because this is the optimal time to quantitate
ovulation rate (our unpublished observation).
Differential display protocols for detection of Egr-1
The steps of the differential display were carried out as
described previously (8). In brief, RNA was extracted by a standard
guanidine isothiocyanate/cesium chloride procedure. RT-PCR was
performed using an RNAimage Kit (G502, GenHunter Corp., Nashville, TN).
The specific primer set that yielded differentially expressed
complementary DNA (cDNA) for Egr-1 was 5'-HTTTTTTTTTA-3' and
5'-HTAGAGCG-3', where H represents a HindIII restriction
site attached to the primers. After extraction and reamplification of
the differentially expressed cDNA, a standard Northern analysis was
performed to confirm the ovulation-specific expression of the parent
mRNA for Egr-1. The unique cDNA fragment was subcloned using a pCR-TRAP
Cloning System (P404, GenHunter), and a cloning colony containing the
Egr-1 cDNA was identified by secondary Northern analysis. Manual
sequencing of the cDNA was performed using a Sequenase version 2.0 DNA
sequencing kit (US70770, Amersham Pharmacia Biotech,
Piscataway, NJ). In situ hybridization was performed as
described previously (8).
Western blot analysis of Egr-1
Ovaries were extirpated from rats at the indicated periovulatory
intervals, and granulosa cells were isolated from the residual ovarian
compartment by puncture with a 26-gauge needle. Whole cell extracts
were prepared from cells and tissue by homogenizing in 10
mM Tris-buffer (pH 7.5) containing 0.4 M NaCl,
1 mM dithiothreitol, and 10% glycerol. The Tris buffer
also contained phosphatase and protease inhibitors in amounts of 1
mM EDTA, 1 mM phenylmethylsulfonylfluoride, 1
mM orthovanadate, 10 mM NaF, 10
µM leupeptin, 10 µM pepstatin, and 1
µg/ml aprotinin. Protein extracts (50 µg) were resolved by reducing
SDS-PAGE on a 10% acrylamide gel and transferred to polyvinylidene
difluoride membranes (Immobilon-P, Millipore Corp.,
Bedford, MA). To minimize nonspecific binding, the membranes were
shaken for 1 h in 3% nonfat milk, incubated for 1 h in 3%
milk with 0.5 µg/ml Egr-1 antiserum (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), and subsequently washed in TBST [10
mM Tris (pH 7.5), 150 mM NaCl, and 0.05%
Tween-20]. Blots were then incubated for 1 h with 1:10,000
horseradish peroxidase-linked antirabbit IgG (Amersham Pharmacia Biotech). After incubation, the membranes were washed again in
TBST, and Egr-1 detection was performed according to the
manufacturer’s instructions.
Statistical analysis
The intensity of the signals from the Northern blots was
quantitated by the NIH Image densitometry program, as described
previously (8). Numerical data are presented as the mean ±
SEM. The significance of the differences among means was
determined by Duncan’s multiple range tests after a completely
randomized one-way ANOVA of the means of the groups. The cut-off
between significant and not significant was P =
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Therefore, the most intense cDNA band
(i.e. the band in the 4 h lane) was excised from the
acrylamide gel and reamplified for use as a probe in Northern analysis
and for in situ hybridization.
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). In view of the fact that the initial
Northern analysis revealed that the onset of Egr-1 mRNA expression
began at some point between 0 and 2 h after the hCG stimulus, a
subsequent set of RNA extractions included time points of 0.5 and
1 h. As the most intense Northern signal was at 4 h, the
value for this lane was arbitrarily set at 100%, and the densities at
the other times during the periovulatory period were expressed as
fractions of that maximum. Accordingly, the NIH Image program was used
to digitize all of the bands on the Northern blots, and the ratio of
the density of each experimental band to its corresponding ß-actin
control band was calculated for each lane. Based on these calculations,
Egr-1 gene expression increased 39-fold within 4 h after the
ovulatory process was initiated by an injection of hCG into the
animals. Subsequently, at 24 h after hCG (i.e. during
early luteal development), Egr-1 gene expression declined to a level
that was not significantly different from the 0 h control
value.
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Effects of indomethacin and epostane on Egr-1 gene
expression
For these tests, Northern blots were prepared from RNA extracted
from control ovaries at 0 and 4 h after injection of hCG or
extracted from experimental ovaries taken at 4 h after hCG from
rats that had been treated 1 h earlier with ovulation-inhibiting
doses of indomethacin or epostane. The experimental interval of 4
h after hCG was selected because this time coincided with the time of
maximum expression of the Egr-1 gene (Fig. 2
). The signal density
(normalized against the ß-actin control) of the 4 h control lane
was arbitrarily set at 100% (Fig. 3).
There was minimal expression of Egr-1 mRNA at 0 h, but substantial
expression at 4 h. In animals treated with the antiovulatory agent
indomethacin, which blocks prostanoid synthesis, signal density was not
significantly different from the 4 h control value. Animals
treated with the antiovulatory agent epostane, which blocks
progesterone synthesis, had a signal density that was moderately higher
than yet statistically different from the 4 h control value. The
ovulation rates in parallel groups of animals treated with either
indomethacin or epostane were significantly lower, i.e. were
inhibited by these agents (Fig. 3). In additional parallel groups of
animals, indomethacin significantly inhibited ovarian
PGE2 synthesis, and epostane significantly
inhibited ovarian progesterone synthesis (Fig. 3). Thus, indomethacin
and epostane inhibited ovarian prostanoid and steroid synthesis,
respectively, in a predictable manner, without affecting Egr-1 gene
expression.
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). Hybridization was
localized in the granulosa layer of the larger follicles along with
what appeared to be some hybridization in the theca interna (Fig. 5). A number of smaller follicles
(located mainly in the center of the ovaries) had no detectable Egr-1
mRNA. Most of the other smaller follicles that did exhibit
hybridization had thicker granulosa layers, indicating that these
probably were large mature follicles that happened to be sectioned on a
plane that was above or below their maximum diameter.
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). As predicted by the in
situ data, the isolated granulosa cells evinced a substantial
amount of Egr-1. The modest expression of Egr-1 in the residual ovarian
tissue may have been generated by cells in the theca interna, but we
cannot rule out the possibility that the source of this Egr-1 was
granulosa cells that invariably remain in the residual portion of the
ovary. The size of the translated protein was 84 kDa.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Transcription of the Egr-1 gene appears to be regulated by multiple signal transduction processes, including the protein kinase C pathway (4). However, the protein kinase A pathway is the most likely path activated by the LH surge in granulosa cells (2, 3). The promoter region of the Egr-1 gene contains an Sp1-binding site that can confer trans-activation by Sp1 as well as by chicken ovalbumin upstream promoter transcription factor (COUP-TF) (13). Sp1 is expressed at high levels in granulosa cells, and Sp1-binding sites in the promoters of several ovarian-expressed genes have been shown to confer FSH and LH inducibility (2, 14). In some cells, the activation process occurs within minutes. For example, in quiescent fibroblasts that have been stimulated by FCS, there is detectable Egr-1 expression as early as 10 min. In this 3T3 cell model, expression reaches a peak within 30 min and then declines to basal levels by 3–4 h (4). In contrast, ovarian expression of Egr-1 mRNA and its protein product appears to peak approximately 4 h after initial stimulation of the ovulatory process by hCG, and expression of this immediate-early gene does not return to basal level until sometime between 12 and 24 h after hCG. The difference in the relative time course of Egr-1 expression in the ovary compared with that in 3T3 cells in culture may depend on the time required in vivo to increase intracellular levels of hormone, the stage of cell differentiation, or other contextual controls in ovarian cell function. Importantly, granulosa cells of preovulatory follicles respond to LH (or hCG) by rapid exit from the cell cycle and rapid entry into a program of terminal differentiation to luteal cells (15, 16), whereas the 3T3 cell model is poised for cell proliferation (4). It has been suggested that the poststimulus return to the basal level is the effect of some autoregulatory mechanism (4).
The Egr-1 gene product is a member of the zinc finger family of transcriptional regulators that bind specific sequence motifs in gene promoters. Egr-1 is unique in that it can regulate transcription of some genes positively while affecting other genes negatively (4, 11). Also, it should be noted that Egr-1 has a serine- and threonine-rich repressor domain that may dominate the transcriptional phenotype of the Egr-1 molecule in the absence of phosphorylation activity that is usually generated by signal transduction processes. This possible bifunctional nature of Egr-1 has been described in more detail previously (4). The importance of the present discussion to future studies on ovarian genes regulated by Egr-1 is that target genes may be either activated or repressed, depending on the pattern of phosphorylation of the Egr-1 transcription factor as well as the promoter composition of the target genes.
It is interesting to note that the immediate-early gene response that generates Egr-1 includes a slightly deferred induction of genes for NGFI-A-binding proteins, a family of corepressors that binds directly to Egr-1 and repress Egr-1-mediated transcription (17, 18, 19). Thus, the cascade of transcriptional activity that is induced by Egr-1 is transient, not just because Egr-1 gene expression is down-regulated, but also because the Egr-1 protein interaction with general transcriptional effectors becomes altered. Such transient transcriptional activity is relevant to the present experimental model because the ovulatory process has been likened to an early transitional phase of the luteinization process that is induced by gonadotropic hormones (1, 2). Therefore, it is possible that the downstream repertoire of Egr-1-induced growth signals could include a subset of genes that is responsible for temporary degradation of the ovarian follicle as it metamorphoses into a functional corpus luteum.
The ubiquitous nature of Egr-1 expression as an early response to growth signals suggests that this zinc finger transcription factor has a pivotal role in a cascade of gene expression in cells that have been induced to undergo proliferation, differentiation, or responses to inflammatory-like signals. There is a growing list of physiologically relevant genes that are now recognized as targets for Egr-1 (4, 5, 7, 20, 21). Some targets that are related to proliferative responses include the thymidine kinase gene that peaks during late G1; various growth factor genes, such as platelet-derived growth factor and fibroblast growth factor; the interleukin genes; and the tumor necrosis factor genes. Others, such as the LHß gene, the family of cell surface adhesion protein genes for CD44, and genes for several matrix metalloproteinases (MMPs), are related more to differentiated functions of these cells. The reported relationship among Egr-1, CD44, and a number of MMPs (21, 22, 23, 24) is especially intriguing, because this family of proteases has been implicated in the degradative events of ovulation for quite some time (25). MT1-MMP (i.e. MMP14) is the only one to date that has been shown to have a functional Egr-1 site in its promoter (21). MMP14, which has been demonstrated in several different types of cells, initially decreases in granulosa cells within 4 h after stimulation by hCG, and then it increases at 12 h after hCG (26). Therefore, MMP14 might be negatively or positively regulated by Egr-1 in luteinizing granulosa cells. In contrast, ADAMTS-1 (25), MMP19 (26), and tissue inhibitor of metalloproteinase-1 (26) are all induced by hCG, making them possible targets of Egr-1 in granulosa cells and possibly in theca interna cells. In any event, these and other genes that have been linked to Egr-1 are all candidates for investigation as potential mediators of Egr-1 action in ovarian follicles during the ovulatory process.
The present assessment of ovarian Egr-1 gene expression compared with ovarian PGE2 and progesterone levels was conducted because of the extensive evidence that the synthesis of such prostanoids and steroids begins to increase in the ovary around 2–3 h after initiation of the ovulatory process by hCG (1, 9). The existing evidence shows that ovarian PGE2 and progesterone increase to peak at approximately 8–10 h after initiating the ovulatory process with hCG. Therefore, it was necessary in this study to rule out the possibility that inhibition of PGE2 by indomethacin or inhibition of progesterone by epostane might also inhibit Egr-1 gene expression. However, the results make it clear that ovulation-inhibiting doses of indomethacin or epostane that significantly reduce ovarian prostanoid and steroid synthesis, respectively, do not affect Egr-1 gene expression during the early stages of the ovulatory process. Thus, it appears that Egr-1 gene expression is not influenced by ovarian prostanoid or steroid production during ovulation.
In conclusion, Egr-1 expression is an immediate-early gene response to gonadotropic hormone action on ovulatory follicles. This gene expression is not dependent on the well known increases in ovarian PG or progesterone synthesis during ovulation. The in situ hybridization data indicate that Egr-1 gene expression is localized in the granulosa layer, and possibly in the theca interna layer, of the larger antral follicles. This suggests that the transcription factor that is translated from the Egr-1 gene may have a central role in regulating the rapid reprogramming of follicular cells to luteal cells (2, 15). There is also evidence linking Egr-1 activity to sites of inflammation (10, 20, 27, 28, 29). Therefore, as the ovulatory process is comparable to an acute inflammatory reaction (30), Egr-1 might serve as a mediator of the transient events that cause degradation and rupture of a follicle. It will be of particular interest to assess the potential of Egr-1 protein as a transcription factor for MMP gene expression in follicular tissue at the time of ovulation. Finally, it has been reported that Egr-1 is important for female fertility, because it regulates LH expression in the pituitary gland and LH receptor expression in the ovary (31, 32). The present results indicate that Egr-1 may also affect fertility by initiating a cascade of ovulation-specific gene expression in ovulatory follicles that have been stimulated by gonadotropic hormone.
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Footnotes |
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Received December 27, 1999.
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References |
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-induced transcriptional activation of the vascular
permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding
and transactivation. EMBO J 16:750–759[CrossRef][Medline]
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S. Yoshioka, S. Ochsner, D. L. Russell, T. Ujioka, S. Fujii, J. S. Richards, and L. L. Espey Expression of Tumor Necrosis Factor-Stimulated Gene-6 in the Rat Ovary in Response to an Ovulatory Dose of Gonadotropin Endocrinology, November 1, 2000; 141(11): 4114 - 4119. [Abstract] [Full Text] [PDF]
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