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Female Reproductive Tract |
a Departments of Obstetrics and Gynecology,
b Physiology and Biophysics,
and
c Medicine, University of Illinois at Chicago College of Medicine and VA Chicago Healthcare System (West Side), Chicago, Illinois 60612
d Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520
e CNRS UMR 8542, Ecole Normale Superieure, Paris, France
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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decidua, female reproductive tract, gene regulation, implantation, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Multiple factors contribute to the regulation of IGFBP-1 gene expression, including insulin, glucocorticoids, progesterone, cytokines, and hypoxia [1, 6–8]. Recent studies have revealed that FKHR, a member of the FOXO subfamily of forkhead/winged-helix family of transcription factors, plays an important role in mediating effects of insulin on IGFBP-1 promoter activity in liver-derived cells [9–12]. FKHR binds directly to insulin response sequences (IRSs) in the proximal IGFBP-1 promoter, whereas phosphorylation of FKHR by protein kinase B (PKB) and other phosphatidylinositol-3' kinase-dependent kinases suppress transactivation by FKHR, thereby inhibiting IGFBP-1 expression [9]. Recent studies have revealed that FKHR is induced in differentiating human endometrial stromal cells [13]. Based on these findings, we asked whether FKHR might contribute to the regulation of IGFBP-1 in uterine cells.
Homeobox (HOX) proteins are developmentally regulated transcription factors that are important in spatial identity and differentiation of tissues in the developing embryo. These genes contain a common sequence of 183 base pairs (bp), known as the homeobox, which encodes for a highly conserved 61-amino acid homeodomain. Homeodomain proteins can activate or repress the expression of target genes [14]. In the developing reproductive tract, four genes of the HOXA cluster (HOXA9, HOXA10, HOXA11, and HOXA13) are expressed [15]. HOXA10 is expressed in the developing uterus, specifically in the endometrial glands and stroma of the endometrium, where its expression is dependent on the stage of the menstrual cycle, which dramatically increases at the time of implantation [15–17]. HOXA10-deficient mice exhibit uterine factor infertility due to implantation defects. Specifically, decidualization of the endometrium is severely compromised during blastocyst implantation [18]. It is interesting that the IGFBP-1 gene is located in close proximity to the HOXA gene cluster on chromosome 7, suggesting evolutionary linkage of the IGFBP and HOX gene families.
Recent studies have suggested that overexpression of HOXA5 in transgenic mice up-regulates IGFBP-1 expression in the liver [19]. However, the role of HOX proteins in regulating the IGFBP-1 gene in the differentiating endometrium is unknown. Since HOXA10 [17] and FKHR [13] are expressed in human endometrial stromal cells, we asked whether HOXA10 and FKHR contribute to IGFBP-1 regulation in primate endometrial stromal cells. Here, we show that FKHR and HOXA10 follow similar patterns of expression during different stages of the baboon menstrual cycle and pregnancy. Reporter gene studies indicate that FKHR and HOXA10 function cooperatively to stimulate baboon and human IGFBP-1 promoter activity, and direct physical association between FKHR and HOXA10 is observed in glutathione S-transferase (GST) pull-down studies. Together, these findings indicate that FKHR and HOXA10 may play an important role and function cooperatively in regulating the expression of IGFBP-1 and perhaps other genes in the primate endometrium.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Midluteal phase (9–11 days postovulation [PO]) endometrial tissue was obtained from adult female baboons (Papio anubis) by endometriectomy or hysterectomy. All animal studies were approved by the Animal Care Committee at the University of Illinois at Chicago. Stromal cells were isolated from baboon endometrial tissues as described previously [4].
HuF cells were isolated from decidua parietalis dissected from the placental membranes after normal vaginal delivery at term, as previously described [5]. Decidualized uterine endometrium maintains a proliferating population of predecidual fibroblastic cells, which closely resemble stromal cells [20, 21]. These cells were passaged as needed up to a maximum of seven passages.
RNA Isolation and Analysis
Tissue was homogenized in TriReagent (Molecular Research Center Inc., Cincinnati, OH) and RNA was extracted using the protocol provided by the manufacturer. One microgram of total RNA was reverse transcribed and polymerase chain reaction (PCR) amplification was performed for 33 cycles using FKHR primers and 24 cycles using H3.3 primers under conditions previously described [4, 9]. PCR products were electrophoresed in 1% agarose gel containing ethidium bromide. Densitometric analysis of the PCR products was performed using the EDAS 290 Imaging System (Kodak, New York, NY). The densitometric values were normalized to H3.3. For Northern blotting, total RNA (40–50 µg) was size fractionated on 1% agarose/0.66 M formaldehyde by gel electrophoresis and transferred to nylon membranes. Membranes were hybridized at 68°C in Perfecthyb buffer (Sigma, St. Louis, MO), 0.2% tRNA, and 32P-labeled riboprobe at 2 x 106 cpm/ml. The filter was washed twice at 60°C for 20 min in 0.1x saline-sodium citrate (SSC) and 0.1% sodium dodecyl sulfate (SDS). X-Omat AR (Kodak) was exposed overnight at -70°C. The autoradiographic bands were quantified using a laser densitometer. Each HOXA10 band was normalized to the value obtained from the same lane hybridized to GAPDH.
Cloning and Sequencing of the Baboon IGFBP-1 Promoter Region
Colony lifts of an amplified male baboon kidney tissue genomic DNA Lambda Dash II library were screened with a randomly labeled 1.2-kilobase (kb) human IGFBP-1 cDNA probe [22]. Positive clones were subjected to two further rounds of screening. The insert was isolated on agarose gels and cloned into the NotI site of pBluescriptII SK-. A HindIII subfragment containing approximately 4 kb of the 5'-flanking region through the start of transcription was subcloned into the same vector. The 4-kb fragment was sequenced by dideoxy sequencing at the University of Illinois at Chicago Sequence Center. This gene sequence was deposited in GenBank under accession number AY095345.
Reporter Gene Constructs and Expression Vectors
A region spanning -358 to +75 relative to the transcription start site was isolated by PCR from both human and baboon IGFBP-1 promoters using as templates, the human p3.6BP1.CAT plasmid (a gift from D. Powell, Lexicon Genetics Inc., The Woodlands, TX) and the cloned 4-kb baboon promoter fragment, respectively. The 5' primer corresponded to bases -358 to -339 of the human sequence (accession number M59316) and additional bases were added to the 5' end of the primer to create an XhoI site. The 3' primer corresponded to bases +58 to +75, including additional bases at the 3' end to create a HindIII site. The PCR product was subcloned into the XhoI/HindIII sites of the promoterless pGL3-basic vector (Promega, Madison, WI). The promoter fragments were verified by dideoxy sequencing. The human pHbp1-358.Luc and baboon pBbp1-358.Luc constructs were then used for transient transfections. For construction of mutated IRS constructs, the pHbp1-358.Luc was first truncated to the region spanning -224 to +75 (pHbp1-224.Luc) by PCR. IRSA (-118 to -111) and IRSB (-108 to -101) in the pHbp1-224.Luc construct were mutated (pHbp1-224/IRSABmut.Luc) using the QuikChange site-directed mutagenesis kit (Stratagene, La Jolla, CA) (Fig. 5). For the construct in which only the IRSAB region (-118 to -101) remained, sequences flanking the IRS region (-358 through -119 and -100 through -32) were deleted as shown in Figure 5 using the QuikChange kit, resulting in the plasmid pHbp1-31/IRS.Luc. The IGFBP-1 minimal promoter (-31 to +75) was isolated by PCR using pHbp1-358.Luc as the template and subcloned into the XhoI/HindIII sites of the pGL3-basic vector. All sequences were verified by dideoxy sequencing. The human FKHR expression vector used in these studies is the mutant form in which the three consensus PKB phosphorylation sites, Thr-24, Ser-256, and Ser-319 were mutated to alanines to create a constitutively active form [9]. The DNA binding-defective FKHR expression vector (FKHR-Helix 3.2M) containing a mutation of Trp-209 to Gly and His-215 to Pro has been previously described [23]. The HOXA10 cDNA was a gift from C. Largman (University of California VA Medical Center, San Francisco, CA), which was subsequently inserted into the EcoRI site of pcDNA3.1 (+) (Invitrogen, Carlsbad, CA) by H. Taylor.
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Cell Transfection and Reporter Gene Studies
Transient transfection of baboon endometrial stromal cells and HuF cells grown in 12-well plates was performed using Lipofectamine 2000 (Invitrogen). Cells were transfected in Dulbecco modified Eagle medium with 1 µg/well of the IGFBP-1 promoter constructs with or without 0.5 µg/well FKHR, 0.5 µg/well HOXA10 expression vectors (or both) and pcDNA3.1(+) as an empty vector. After 4 h, the media was changed to RPMI-1640 (Invitrogen) and cells were incubated for an additional 20 h. Cell extracts were harvested and luciferase activity was measured with the luciferase reagent kit (Promega). Transfections were performed in triplicate and experiments were repeated at least three times.
GST-Pulldown
Bacterially expressed GST and GST-FKHR recombinant proteins were purchased (Upstate Biotechnology, Waltham, MA). 35S-Labeled HOXA10 protein was prepared by in vitro transcription-translation using the TNT T7 Coupled Reticulocyte Lysate System (Promega) and 35S-methionine (Amersham Pharmacia Biotech, Piscataway, NJ). Glutathione-sepharose beads (Amersham Pharmacia Biotech) were washed three times with binding buffer (50 mM Hepes, 100 mM NaCl, 20 mM Tris-HCl pH 8.0, 0.1% Tween-20, 10% glycerol, 1 mM dithiothreitol, 0.5 mM phenylmethylsulfonyl fluoride, 0.3 mM sodium vanadate, 1 mM NaF, 5 µg/ml aprotinin [24]). Equimolar amounts of GST-FKHR or GST were preincubated with washed glutathione-sepharose beads in binding buffer for 1 h at 4°C on a rocker platform. Beads were washed twice with fresh binding buffer. 35S-labeled HOXA10 was added to the beads and incubated on a rocker for 3 h at 4°C. Beads were washed three times with binding buffer containing 0.5% IGEPAL (Sigma), resuspended in SDS-polyacrylamide gel electrophoresis buffer, boiled for 5 min, and resolved by 10% SDS-polyacrylamide gel electrophoresis. The input 35S-HOXA10 protein was diluted 1:10 before loading onto the gel. The presence of 35S-HOXA10 was detected by autoradiography.
Statistical Analysis
A paired t-test was performed to compare the effects of FKHR, HOXA10, or both on IGFBP-1 promoter activity compared to control (basal IGFBP-1 promoter activity). The mean values obtained for FKHR alone or HOXA10 alone were also compared to the effects of FKHR + HOXA10 using the paired t-test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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FKHR mRNA levels were examined in the baboon endometrium at various stages of the menstrual cycle and pregnancy by reverse transcriptase-PCR (Fig. 1A). Late follicular phase endometrium exhibited the lowest level of FKHR mRNA. By midluteal phase of the menstrual cycle (Day 10 PO), FKHR mRNA abundance increased. Levels of FKHR mRNA levels were highest in pregnant endometrium and remained high until term (term decidua; Fig 1B). As shown in Figure 1C, HOXA10 mRNA levels were examined in baboon endometrium by Northern blotting. Follicular phase endometrial tissue expressed the lowest amount of HOXA10 mRNA, and HOXA10 mRNA levels were increased in luteal phase tissues (Days 8–14 PO). HOXA10 mRNA abundance was highest in pregnant endometrium and remained high at term (Fig. 1D) following a similar pattern to FKHR expression (Fig 1, A and B).
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Cloning of the Baboon IGFBP-1 Promoter
In order to determine whether FKHR and HOXA10 might stimulate the expression of IGFBP-1 in baboon endometrium, a 
4-kb fragment of the 5'-upstream region of the baboon IGFBP-1 gene was cloned and sequenced and deposited in GenBank under accession number AY095345. A smaller fragment (-358 to +75) was cloned into PGL3-basic vector (Bbp1-358.Luc) for transient transfection studies (Fig. 2). Alignment with the human IGFBP-1 promoter shows that this region is highly conserved, exhibiting 96% identity between baboon and human sequences (Fig. 2). Several hormone response elements including a cAMP responsive element (CRE), two insulin response sequences (IRSA and IRSB), two glucocorticoid/progesterone response elements (GRE/PRE1, GRE/PRE2) [8, 25, 26], and an HNF-1 binding site [27] are conserved in human and baboon IGFBP-1 promoters.
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Regulation of the IGFBP-1 Promoter by FKHR and HOXA10
To examine the effects of FKHR and HOXA10 on IGFBP-1 promoter activity, we first performed transient cotransfection studies in baboon endometrial stromal cells using the baboon IGFBP-1 promoter reporter gene construct (Bbp1-358.Luc). As shown in Figure 3A, cotransfection with the FKHR expression vector stimulated the activity of the baboon IGFBP-1 promoter 8-fold (P < 0.05), consistent with previous studies indicating that FKHR can stimulate IGFBP-1 promoter function [9, 12]. Cotransfection with a HOXA10 expression vector had limited effect on promoter activity (1.3-fold increase), which was not statistically different from the control. However, coexpression of HOXA10 with FKHR markedly stimulated promoter activity (32-fold increase vs. control; P < 0.05). This stimulation exceeded the sum of the effects observed with FKHR and HOXA10 alone, suggesting that these transcription factors may function cooperatively to stimulate IGFBP-1 promoter activity. The increase observed with FKHR + HOXA10 compared to either FKHR alone or HOXA10 alone was statistically significant (P < 0.05).
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To examine the effects of FKHR and HOXA10 on the human IGFBP-1 promoter, we next performed transfection studies with a luciferase reporter gene construct containing the corresponding region of the human IGFBP-1 promoter (Hbp1-358.Luc) in human uterine predecidual fibroblast (HuF) cells. As shown in Figure 3B, expression of FKHR or HOXA10 alone stimulated the activity of the human IGFBP-1 promoter 6-fold (P < 0.05) and 4-fold (P < 0.05), respectively. Coexpression of FKHR and HOXA10 together resulted in synergistic stimulation of promoter activity (44-fold; P < 0.05), similar to results obtained with the baboon promoter in baboon stromal cells. All subsequent studies were performed using constructs containing the human IGFBP-1 promoter transfected into HuF cells.
Stimulation by FKHR and Cooperativity with HOXA10 Requires Binding to IRSs
In order to determine whether FKHR binding to DNA is necessary for cooperative interactions with HOXA10, we performed transient transfection studies with a DNA-binding-deficient FKHR mutant (FKHR-Helix3.2M; [23]). As shown in Figure 4, cotransfection with the FKHR-Helix3.2M expression vector failed to stimulate Hbp1-358.Luc activity in HuF cells. Coexpression of both HOXA10 and FKHR-Helix3.2M also failed to stimulate Hbp1-358.Luc activity (Fig. 4), indicating that DNA binding by FKHR is required for cooperativity with HOXA10.
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FKHR can interact with either IRSA or IRSB in the IGFBP-1 promoter and stimulate promoter activity [9]. Mutation of both IRSA and IRSB (see Fig. 5 for mutated sequences) disrupted the ability of FKHR to stimulate the activity of a reporter gene construct containing 224 bp of the human IGFBP-1 promoter (Hbp1-224.Luc; Fig. 6A), which is consistent with previous studies in liver-derived cell lines. It is interesting that cotransfection with the HOXA10 expression vector had a modest effect on the activity of the human IGFBP-1 promoter, and this effect was also diminished by mutation of the IRSs, suggesting that HOXA10 may interact with the IRS or with endogenous FKHR or related forkhead proteins in HuF cells to enhance promoter activity in an IRS-dependent fashion. Coexpression studies demonstrated that HOXA10 enhances the effect of FKHR on promoter function and mutation of the IRSs disrupts this effect. These results together indicate that interaction with IRSs in the IGFBP-1 promoter is required for the transactivation by FKHR and for HOXA10 to enhance the effect of FKHR on IGFBP-1 promoter activity.
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To further characterize the role of IRSs in mediating the effects of FKHR and HOXA10 on IGFBP-1 promoter activity, we created a series of deletions in the human IGFBP-1 promoter (Fig. 5). As shown in Figure 6B, deletion of all residues located upstream of the 31-bp minimal IGFBP-1 promoter disrupted the ability of FKHR to stimulate promoter activity and to cooperate with HOXA10. Introducing the IRSs and their flanking sequence immediately upstream of the 31-bp promoter restored FKHR stimulation of promoter function (P < 0.05) and the ability of HOXA10 to enhance this effect (P < 0.05). This result indicates that together with the minimal IGFBP-1 promoter and flanking sequences, IRSs are sufficient to confer the ability of FKHR to stimulate promoter activity and to cooperate with HOXA10.
GST-Pulldown
Because FKHR and HOXA10 can act in a cooperative manner, we considered the possibility that there may be a physical association between these transcription factors. As shown in Figure 7, 35S-labeled recombinant HOXA10 prepared by in vitro transcription/translation interacted with the bacterially expressed fusion protein containing GST in frame with FKHR, but not with GST alone. 35S-Labeled luciferase was run in parallel, and no interaction was observed between this protein and either GST-FKHR or GST alone (results not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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FKHR is expressed in a variety of tissues, including the brain, placenta, testes, and liver [31]. The expression of FKHR in baboon endometrium is shown in this report. The factors that induce FKHR expression, however, remain unclear. Christian et al. [13] have identified FKHR using differential display as one of the major transcripts induced in stromal cells of human endometrium by treatment with 8-bromo-cAMP. 8-Bromo-cAMP treatment causes these stromal cells to decidualize and produce IGFBP-1. This would be consistent with FKHR acting as a transcription factor that regulates IGFBP-1 gene expression in stromal cells during decidualization. It has recently been shown that cAMP mediates the effects of FSH on FKHR expression in ovarian granulosa cells [32]. Interestingly, estradiol enhances FKHR gene expression in granulosa cells [32], suggesting that sex steroids also may contribute to the regulation of FKHR.
Although FKHR has been associated with the regulation of the IGFBP-1 gene in hepatic cells, its role in IGFBP-1 gene regulation in uterine cells has not been previously reported. We find that FKHR stimulates IGFBP-1 promoter activity in endometrial cells and that this effect requires interaction with IRSs in the IGFBP-1 promoter. It has been well documented in HepG2 cells that FKHR stimulates the IGFBP-1 promoter through IRSs [9, 10, 12, 33]. Phosphorylation of FKHR by insulin causes this transcription factor to be retained in the cytoplasm and its exclusion from the nucleus is associated with a loss of target gene expression [34, 35]. Studies with human decidualized cells indicate that FKHR is targeted to the nucleus where it can direct effects on gene expression [13]. Here, we used a mutant FKHR, which is not susceptible to phosphorylation by PKB or related phosphatidylinositol-3'kinase-dependent kinases, allowing for constitutive expression of FKHR in the nucleus. Whether factors associated with decidualization and IGFBP-1 expression regulate the distribution of endogenous FKHR to the nucleus, or its interaction with other nuclear factors, including HOXA10, is under investigation.
Recent studies have shown that FKHR can interact with other nuclear transcription factors, including the estrogen receptor, retinoic acid receptor, and thyroid hormone receptor, and either repress or stimulate transactivation mediated by the different nuclear hormone receptors [24, 36]. In this report we find that HOXA10 enhances the ability of FKHR to stimulate the IGFBP-1 promoter activity, and that these two transcription factors can physically associate with one another. Related studies suggest that HOXA5 can interact directly with FKHR, and we have found that HOXA5 also can function cooperatively with FKHR to stimulate the IGFBP-1 promoter in HuF cells [19]. This suggests that multiple HOX transcription factors might interact with FKHR, and perhaps with other FOXO forkhead proteins. Studies are in progress to identify specific domains and motifs that may mediate interactions between FKHR and HOX family members.
Further studies are required to determine the precise mechanism or mechanisms by which FKHR and HOXA10 function cooperatively to enhance IGFBP-1 promoter activity. It is unclear whether there are separate DNA binding sites for FKHR and HOXA10 in the IGFBP-1 promoter, or whether just one site is required for an FKHR-HOXA10 complex to bind. The present study demonstrates that DNA binding of FKHR is critical for FKHR and HOXA10 to act cooperatively on IGFBP-1 promoter activity. Previous studies have shown that FKHR interacts with IRSs in the IGFBP-1 promoter in a sequence-specific fashion [9, 12]. In the present study we found that interaction with IRS is required for functional cooperation between FKHR and HOXA10, and that the IRS region, together with the minimal IGFBP-1 promoter, is sufficient to mediate these effects. Because FKHR can interact directly with HOXA10, it is possible that this interaction may enhance either the binding of FKHR to IRSs or the recruitment of coactivating factors to this site. Alternatively, HOXA10 may interact weakly with cis-acting sequences in the region of the IRSs or the minimal IGFBP-1 promoter, and interaction with FKHR may help to stabilize HOXA10 binding. DNA binding by HOX proteins is mediated by the homeodomain, a conserved 61-amino acid sequence [37]. Homeodomains often interact with (A+T)-rich DNA sequences [14, 38–41], similar to those found in the region of the IRSs and minimal IGFBP-1 promoter. Electrophoresis mobility shift and supershift studies would help to characterize potential HOXA10 binding sites on the IGFBP-1 promoter and the possibility of a FKHR-HOXA10 complex. However, due to the lack of appropriate HOXA10 antibodies, experiments to test this possibility are not currently feasible.
Previous studies have suggested that DNA-binding by HOX family members may involve interactions with cofactors such as PBX, the mammalian homolog of Drosophila extradenticle [42–44]. PBX proteins bind to DNA cooperatively with mammalian HOX proteins and it is believed that interactions with PBX cofactors may contribute to the regulatory control and refinement of HOX protein function. In the present study we found that HOXA10 by itself has a limited effect on IGFBP-1 promoter activity, but functions effectively in combination with FKHR to enhance promoter activity. It is interesting to speculate that interactions with FKHR may modify the ability of HOXA10 to bind to (A+T)-rich target sites in the IGFBP-1 promoter and stimulate transcription.
Forkhead and HOX transcription factors may play an important role not only in the regulation of the IGFBP-1 gene but other genes as well in the endometrium. Greater expression of FKHR and HOXA10 during late luteal phase and in pregnancy suggests that these transcription factors play a role in regulating the expression of genes associated with implantation and the maintenance of pregnancy. Because FOXO forkhead and HOX proteins are found in a number of other tissues, it is interesting to speculate that members of these transcription factor families also may act coordinately to regulate gene expression in other settings.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Asgerally T. Fazleabas, Department of Obstetrics and Gynecology, University of Illinois at Chicago, 820 South Wood Street, M/C 808, Chicago, IL 60612. FAX: 312 996 4238; asgi{at}uic.edu
Received: 11 July 2002.
First decision: 7 August 2002.
Accepted: 12 August 2002.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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