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Department of Obstetrics/Gynecology and Reproductive Medicine School of Medicine State University of New York at Stony Brook Stony Brook, New York 11794
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Previous studies have shown the progestin- dependent production of IGFBP-1 correlates with its mRNA levels and transcription rate. Thus, we have determined the effect of hPR-A and hPR-B on the production of IGFBP-1 in stromal cells treated with MPA. The production rate in cells uniformly infected with AdPRA (recombinant Ad5- directed PR expression system) was significantly higher (P < 0.001) than the rate in uninfected cells and in cells infected with AdPRB or AdCMV (the Ad5 viral expression vector). This result, in concert with the promoter analysis, provides evidence that hPR-A is a strong inducer for the chromosomal IGFBP-1 gene in endometrial stromal cells.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Progesterone-regulated gene expression in endometrial cells has been extensively studied in many laboratories. However, information about PR isoform-specific gene regulation is limited in this target tissue. We believe that hPR-A is active and perhaps more active than hPR-B on those genes that are extensively expressed in decidual cells. However, in several endocrine-sensitive breast cancer cell lines, hPR-B is a stronger transactivator than hPR-A. In addition, hPR-A acts as a dominant repressor of hPR-B on the progesterone response element (PRE) linked-reporter constructs or mouse mammary tumor virus (MMTV) (3, 4) as well as the endogenous target gene (5). Although hPR-A is not a universal repressor (6), additional information showed that the repression is through the structure-specific interaction with the consensus PRE (7, 8). These findings raise the question of the functional aspects of hPR-A in endometrial stromal/decidual cells. The purpose of this study was to determine the transactivation capacity of hPR-A in endometrial stromal cells by using a progestin-induced gene, human insulin-like growth factor binding protein-1 (IGFBP-1).
The IGFBP-1 gene is activated by progestin, and its gene product is the major secretory protein in decidualized endometrial stromal cells (9, 10, 11, 12, 13). Previous studies have shown that cis-elements PRE1 and PRE2 in the IGFBP-1 promoter are the sites responsible to increase the promoter activity in decidualized endometrial stromal cells (13). However, it is not clear whether the activation is mediated from the predominant hPR-A or from the less dominant hPR-B or both. To determine the capacity of transactivation by the PR isoforms, we have measured the effect of cotransfection of hPR-A or hPR-B expression vector on the IGFBP-1 promoter activity in undifferentiated stromal cells in which PRE1/PRE2 have little activity (13). In addition, the production of IGFBP-1 was measured in stromal cells uniformly transfected with AdPRA or AdPRB. Our results indicate that hPR-A is a stronger transactivator than hPR-B to increase the promoter activity in transient transfection assay and production of IGFBP-1 from the endogenous IGFBP-1 gene in endometrial stromal cells.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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) for most of the
experiments presented in this paper (Table 1 and Figs. 2 to 5). Only three experiments were
carried out using p246CAT and p1.2CAT (Table 1). The promoter activity
was low in cells not treated with MPA (
Figs. 2–5) in agreement with
the previous observation (13). MPA had no significant effect on the
promoter activity in cells cotransfected with the empty vector (Fig. 4, lane 1). MPA increased the promoter activity derived from p246CAT
(n = 2), p275CAT (n = 5), and p1.2CAT (n = 1). The
degree of activation varied from 1.2- to 27-fold compared with cells
not exposed to MPA (Table 1) and had no clear correlation with the
stage of menstrual cycle nor with the length of the promoter. However,
the capacity of transactivation by hPR-A was significantly higher than
that of hPR-B determined in eight specimens (Table 1; 15-
vs. 4-fold increase respectively, n = 8, mean ±
SD p < 0.005).
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; P <
0.001). In contrast, we found that hPR-B was a stronger transactivator
than hPR-A for the promoter of MMTV in endometrial stromal cells (Fig. 2B), which is similar to data observed in cancer cell lines (4). This
result shows that the ligand-activated PR isoforms display a spectrum
of transactivation capacity in different target genes in endometrial
stromal cells. In addition, we found that the promoter activities
derived from p275CAT were similarly induced by hPR-A or hPR-B in HeLa
or HepG2 cells (data not shown). This result showed that the capacity
of PR transactivation on the target gene also varies in different types
of cells.
PRE1 and PRE2 Sites in the IGFBP-1 Promoter Mediate the hPR-A
Function
The PRE1 and PRE2 sites are located in the proximal promoter
region shown in Fig. 1. Previously, we have shown that PRE1 and PRE2
are functional in decidualized stromal cells (13). To determine whether
the action of hPR-A is mediated through these two sites, stromal cells
were transfected with hPR-A and p275CAT and three PRE mutants,
respectively (Fig. 1). Figure 3 shows the
promoter activities derived from the wild-type plasmid p275CAT and
three mutants, mutation of PRE1, PRE2, or both. p275PRE1m or p275PRE2m
reduced the promoter activity to 75% and 45%, respectively, of
the p275CAT (P < 0.05 and <0.001). p275PRE1,2 m,
double mutation at PRE1 and PRE2 sites, decreased the promoter
activity to 15% of the wild type (P < 0.0001) (Fig. 3). These findings indicate that the transactivation of hPR-A is
mediated by both PRE1 and PRE2 sites in the IGFBP-1 promoter.
Transactivation of the IGFBP-1 Promoter by hPR-A Is Dose
Dependent
To test whether differential transactivation of hPR-A and hPR-B on
the IGFBP-1 promoter is caused by the concentration of PR-A or PR-B,
stromal cells were transfected with p275CAT and cotransfected with
various amounts of hPR-A or hPR-B expression vector. The promoter
activity increased by 2.5-, 8-, and 20-fold at concentrations of 0.1,
0.3, and 1 µg hPR-A, respectively (Fig. 4, lanes 1–4). The response to hPR-B was
also dose dependent at the same concentrations (1.5-, 3-, and 4-fold
increase, lanes 5–7, respectively). At a comparable dose, the potency
of hPR-A was always stronger than hPR-B. No self-squelching was shown
within the range tested.
hPR-B Inhibits the Effect of PR-A and Repression Does Not Require
the DNA Binding Domain
To test whether hPR-B would interfere with the action of hPR-A,
cells were transfected with hPR-A alone or a mixture of hPR-B and
hPR-A. Addition of hPR-B reduced the activity by 50% and 60% at the
ratios of hPR-B/hPR-A 0.3 and 1, respectively (Fig. 4, lanes 8 and 9).
These results suggest that hPR-B acts as a repressor to quench the
transactivation of hPR-A. Cotransfection with hPRB-DBDcys, which
produces a mutant hPR-B unable to bind to the DNA, did not reverse the
inhibition (lane 10). The result indicates that inhibition does not
require DNA binding. Data suggest that the inhibition is mediated by
protein-protein interaction, although the exact nature of the
interaction is not clear and requires additional study.
Various Ligands Do Not Change the Relative Capacity of
Transactivation of hPR-A and hPR-B
To test whether the high capacity of hPR-A is ligand specific, the
promoter activity was determined in cells treated with MPA,
progesterone (P), or the 19 nor-progestins: Org2058 and norethindrone.
Although the degree of activation varied among different progestins (5-
to 8-fold), hPR-A was always more potent than hPR-B (Fig. 5). These results show that the high
capacity of transactivation from hPR-A is not caused by a specific
ligand. The antiprogestin, RU-486, caused a moderate increase in cells
co-transfected with hPR-A or hPR-B (1.8- or 1.6-fold increase).
Cortisol had no effect on the promoter activity.
hPR-A Is a Strong Inducer For the Production of IGBFP-1 in
Endometrial Stromal Cells
The findings described in the previous sections were demonstrated
in transient transfection experiments. It is important to provide
evidence whether hPR-A is indeed a strong transactivator for the
endogenous IGFBP-1 gene in stromal cells. Previous studies have shown
that rate of production and mRNA levels correlate with the rate of
transcription of the IGFBP-1 gene (9, 10). Thus, we have determined the
effect of hPR-A and hPR-B on the induction of the endogenous
IGFBP-1 gene in stromal cells. Such experiment requires a high
efficiency of transfection to achieve a uniform gene transfer. To
increase the efficacy, Ad5-recombinant gene transfer technique was used
for this study. Adßgal infection was used as a positive control (Fig. 6D). Stromal cells remained viable after
infection with various Ad5-recombinant constructs. Immunohistochemical
localization showed that approximately 95% of the stromal cells
expressed hPR-A and hPR-B with a similar intensity of staining (Fig. 6, B and C) in the nuclei when the cells were infected with equal amount
of AdPR-A and AdPR-B, respectively (five viral particles per cell).
Twelve days after infection, the intensity was reduced approximately
50%. In stromal cells with no viral infection or infected with the
vector AdCMV, no detectable PR was found under the same experimental
condition (Fig. 6A), indicating that the endogenous hPR is relatively
low compared with the cells infected with AdPRs.
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shows the production of IGFBP-1
in cells infected with five viral particles per cell and then treated
with MPA. IGFBP-1 was undetectable by ELISA in long-term cell culture
(11 days) without MPA treatment in agreement with previous observation
(9). In cells treated with MPA, the production rate was minimal on the
first 6 days of culture, which is similar to the results published
previously (9). The rate was significantly increased after 7 days MPA
treatment (Fig. 7) with no difference between uninfected cells and
cells infected with AdCMV (0.04, 0.25, and 4.4; 0.05, 0.45, and 3.2
µg/1 x 106 cells/day on days 7, 9, and
11, respectively). This result indicates that infection of the Ad5
vector (five particles per cell) did not appreciably alter the
MPA-induced production of IGFBP-1. The production rates in
cells infected with AdPRB (five particles per cell) were also similar
to the rates in uninfected cells. The production rates in cells
infected with AdPRA (five particles per cell) were 0.07, 2.2 to 11
µg/1 x 106 cells/day on days 7, 9, and
11, respectively, which are significantly higher than that of
uninfected cells or Ad5 or Ad5-hPR-B infected cells (P
< 0.01, day 7; P < 0.001, days 9 and 11). These
results indicate that hPR-A, not hPR-B, is a strong transactivator for
the induction of IGFBP-1 production.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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) represses the
activity in endometrial cells (14) but it activates the promoter in
HepG2 cells by HNF1, a liver factor not expressed in stromal cells
(14). More importantly, progestin and its receptor are essential to
activate the endometrial/decidual IGFBP-1 expression (10) whereas
in HepG2 cells, glucocorticoids activate its expression (17, 18).
In this study, we have demonstrated that ligand-activated hPR-A is a
stronger transactivator than hPR-B to increase the promoter activity as
well as the induction of endogenous IGFBP-1 gene in endometrial stromal
cells. The promoter analyses, using transient transfection of a short
promoter fragment, have shown that active sites, PRE1/2, mediate the PR
activation. Also, the response is dose dependent and can be detected
after 2 days incubation with MPA. These data provide evidence that
transactivation of PR is directly interacting on the IGFBP-1 promoter
although indirect effect is also probable. These data imply that the
high production of IGFBP-1 (Fig. 7), although it was slow to rise, is
mediated by interaction of hPR-A with the PRE1 and PRE2 sites.
The delayed effect shown in Fig. 7 is likely caused by the multiple
regulatory elements that prevent an immediate response. For example, we
have shown that CCAAT (-82 to -52 bp) represses the promoter activity
mediated by NF-Ys which was down-regulated by MPA (14). The overall
production of IGFBP-1 is likely resulted from the balance between
activation and repression at transcription and posttranscription levels
(9, 10, 11, 12, 13, 14, 15).
Although overexpression of hPR-A or hPR-B was used in the present
study, we consider that the results are physiologically relevant since
the study was carried out in a primary culture system that depicts
decidualization in vivo (16). Also, no squelching was
observed (Fig. 4). In Fig. 4, we found that hPR-B reduced the hPR-A
activated promoter activity (lanes 5–7, 8, and 9). These results
coincide with the low production rate in the first 6 days of culture
with MPA and in undifferentiated stromal cells (9) since they contain
an equivalent amount of hPR-A and hPR-B (1). The high promoter activity
and production rate activated by PRA (Fig. 3, lanes 2–4, and Fig. 7)
correlate with the exponential increase of the IGFBP-1 production and
mRNA level in decidualized stromal cells (9, 10) where hPR-A is
predominant (1, 2). Taken together, the present findings illustrate, at
least in part, the induction mode of IGFBP-1 gene in endometrial
stromal/decidual cells, i.e. activation of the endometrial
cell IGFBP-1 gene is progestin dependent and mediated by the content of
the PR isoforms at different stages of stromal cell decidualization.
Other factors, such as Sp3 and CCAAT binding proteins, also regulate
the transcription (12, 13, 14, 15, 16), which may be either dependent or
independent on the progestin regulation.
In comparison, hPR-B transactivates the pMMTV-CAT stronger than that of
hPR-A in stromal cells (Fig. 2B). Our observations, together with data
obtained in cancer cell lines (3, 4, 5, 6, 7, 8), indicate that the two PR isoforms
can have dissimilar responses to different promoters. In addition, we
have shown that hPR-B acts as a transdominant repressor of hPR-A in
contrast to the findings in cancer cell lines (3, 4, 5). Since the
repressor "domain" resides in both isoforms (6, 7, 8), the repressive
effects of the two isoforms appear to be also relative depending on the
target genes and cell context.
At present, the molecular mechanism of the high transactivation capacity of hPR-A for the IGFBP-1 promoter is unclear. It may be due to the differences in binding capacity or affinity of hPR-A/hPR-B to PRE1/PRE2 sites. However, our binding analysis ruled out this possibility. It is likely due to its interaction with the adjacent sequences of PRE1 and PRE2 or its interaction with other factors associated with these two regions in stromal cells.
The high capacity of hPR-A to transactivate the IGFBP-1 gene suggests that endogenous hPR-A in decidual cells may be also active on the other genes expressed in endometrial/decidual cells. Previous studies have shown that progestin induces aromatase, fibronectin, IGFs, PRL/PRL-R, hPRs, and IGFBP-1 to a moderate degree in the predecidual cells. Among these genes, only hPR-A, PRL, PRL-R, IGFBP-1, and IGF-II are extensively induced in decidual cells (1, 9, 10, 11, 12, 13, 14, 15, 16, 19, 20, 21, 22). The continuous induction of these genes could be associated with the high transactivation capacity of hPR-A directly or indirectly acting on the target genes. Interestingly, preliminary data showed that hPR-A is also a strong transactivator for the production of PRL (our unpublished observation). Further study is needed to clarify the PR isoform specific for gene activation in this system.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Plasmid Constructs and Transfection Assay
IGFBP-1 promoter-reporter constructs p275CAT and p1.2CAT [the
promoter regions between -275 to +68 bp and -1.2 kb to +68 linked to
the chloramphenicol acetyl transferase (CAT) reporter gene] were
constructed previously (Fig. 1 and Ref. 13). Both constructs contain
the PRE1 and PRE2 sites, which are located at -193 to -179 bp and
-102 to -88 bp of the IGFBP-1 promoter, respectively. Mutants
(p275PRE1.2 m, p275PRE1m, and p275PRE2m) were constructed previously by
double or single mutation at core sequence of the PRE1 and/or PRE2 site
(Fig. 1). hPR-A and hPR-B expression vectors were a gift from Dr. P.
Chambon (24). hPRB-DBDcys, a construct of PR-B
DNA binding mutation, was provided by Dr. K. Horwitz (25). pMMTV-CAT
(containing two sets of consensus PRE) and pRSV-luc were also used
(26, 27, 28). Plasmids were purified twice by CsCl/ethidium bromide
gradient centrifugation before use. After transfection, cells were
cultured without or with MPA for 2 days and then harvested in 0.15 ml
lysis buffer (Promega Corp., Madison, WI). The promoter
activity (CAT) was measured in a reaction mixture of cell lysis, 0.1
µCi [3H]acetyl coenzyme A (NEN Life Science Products, Boston, MA) and chloramphenicol at 37 C in 0.2
ml buffer solution containing 0.12 M Tris, pH 6.8. The
reaction was stopped by adding 25 µl of 2 M perchloric
acid and counted in 3 ml of ScintiLene (Fisher Scientific,
Pittsburgh, PA) by a Beckman Coulter, Inc. scintillation
counter. The CAT activity was normalized to luciferase activity derived
from pRSV-Luc cotransfected with the promoter construct. The Luc
activity was measured by Luminometer (Fluoroskan Ascent, Fl, Labsystem
OY, Helsinki, Finland). Each experimental design was confirmed in at
least two independent experiments. Representative results are
summarized in the present report. Data are presented as mean ±
SD calculated from triplicate dishes.
Construction and Infection of AdPRA and AdPRB and IGFBP-1
Assay
Recombinant adenoviral transfer vector containing hPR-A or hPR-B
under the control of the cytomegalovirus (CMV) was constructed
according to the established procedures (29, 30, 31). A
replication-defective human adenovirus, Ad5 [lacking E1A and E1B,
replication incompetent in normal mammalian cells (29, 30)], was used
for the construction of AdPRA and AdPRB. Briefly, hPR-A and hPR-B cDNAs
were separately cloned into plasmid [pACsk2CMV5 (31)], containing
CMV-1 promoter and adenovirus sequences to yield pACsk2CMV-PRA, and
pACsk2CMV-PRB, respectively. The recombinant plasmids and pJM17 (29)
were transfected into human embryo kidney cells (293 cells) by
lipofectamine (Life Technologies, Inc., Gaithersburg,
MD). The two plasmids were recombined at the overlapping viral
DNA sequence to yield a recombinant packageable viral genome. Positive
viral plaques with hPR-A or hPR-B insert were identified and then
propagated to produce large quantities of the recombinant AdPRA and
AdPRB, respectively. Titered viral stocks were used to infect the
endometrial stromal cells. Cells (1 x 106
cells per dish) were incubated with recombinant viral particles (1, 5,
10, or 50 particles per cell) to achieve an optimal infection. Ninety
five percent of the cell population was infected by Ad5 viral particle
as shown in Fig. 6.
To identify recombinant PR, stromal cells infected with AdPRA and AdPRB were incubated with MPA 2 to 12 days. Cells were then processed for immunohistochemistry using Mab hPRa3 provided by Dr. P. Satyaswaroop (32) and the Histostain SP-kit detection system (Zymed Laboratories, Inc. South San Francisco, CA) described previously (1). Cells infected with Adßgal were stained with substrate X-gal solution (United States Biochemical Corp., Cleveland, OH). The IGFBP-1 in culture medium was measured by ELISA (9) from stromal cells infected with equal amount of viral particles, Ad5, AdPRA, and AdPRB, respectively.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Supported by NIH Grant HD-19247.
Received for publication May 25, 2000. Revision received August 15, 2000. Accepted for publication August 23, 2000.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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