Mol. Hum. Reprod. Advance Access originally published online on February 16, 2004
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Molecular Human Reproduction, Vol. 10, No. 4, pp. 223-228, 2004
© European Society of Human Reproduction and Embryology 2004
Expression pattern of the activating protein-1 family of transcription factors in the human placenta
1Institute of Pathology, Department of Gynaecopathology, 2Department of Medicine, University Hospital Eppendorf, Hamburg, Germany and 3Department of Obstetrics and Gynecology, University of Iraklion, Greece
4 To whom correspondence should be addressed at: Institute of Pathology, University Hospital Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. e-mail: abamberger{at}uke.uni-hamburg.de
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The human placenta is a tissue with a unique capacity for rapid, but—as opposed to malignant tumours—tightly controlled
proliferation and invasion capacity. The members of the activating protein-1 (AP-1) family of transcription factors are key regulators of cellular proliferation, differentiation and invasion processes in many systems and could, thus, play an important role in regulating these processes in the human placenta as well. In the present study, we used immunohistochemistry with specific antibodies against all members of the AP-1 family (c-Jun, JunB, JunD and c-Fos, FosB, Fra-1, Fra-2) to investigate their expression pattern and tissue localization in the human placenta. With the exception of c-Jun, which was expressed in a small fraction of villous cytotrophoblast nuclei and JunD, expressed in some syncytiotrophoblast nuclei, all other members of the AP-1 family were completely absent from villous cyto- and syncytiotrophoblast. Interestingly, most AP-1 factors were expressed in the intermediate (extravillous) trophoblast, with expression being strongest for JunD and Fra2 (100% of nuclei showing strong expression), followed by c-Jun (80% positive nuclei), c-Fos and FosB (50% positive nuclei). This was true for samples of both first trimester and later pregnancy. These data show that, in the human placenta, the AP-1 transcription factors are specifically expressed in the intermediate (extravillous) trophoblast, were they could be implicated in regulating proliferation, differentiation and/or expression of invasion-specific molecules, such as matrix metalloproteinases, which have been shown to be regulated by AP-1 in vitro and are expressed by the invasive trophoblast. Key words: Key words: activating-protein-1/Fos/human/Jun/placenta
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Introduction |
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TopABSTRACTIntroductionMaterials and methodsResultsDiscussionREFERENCES |
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The human placenta posseses, through its capacity to proliferate and to invade maternal tissue, qualities which are usually found in malignant tumours. However, proliferation and invasion at the maternal–fetal interface are tightly regulated and, in fact, malignant tumours derived from placental tissue are fairly rare (Bamberger and Bamberger, 2002). Transcriptional regulation of these processes is so far poorly understood.
The composite transcription factor activating protein-1 (AP-1) is the prototype of a mitogen-activated transactivator, and its transcriptional activity is believed to reflect cell proliferation in many tissues and also to regulate the expression of invasion-associated genes (Miller et al., 1984; Schutte et al., 1989; Angel and Karin, 1991; Pfahl, 1993; Ozanne et al., 2000; Shaulian and Karin, 2002). It is a homo- or heterodimeric DNA-binding protein composed of either two Jun family proteins (c-Jun, JunB, JunD) or one Jun and one Fos family protein (c-Fos, FosB, Fra-1, Fra-2) (Ransone and Verma, 1990; Angel and Karin, 1991; Karin et al., 1997; Shaulian and Karin, 2002). The activity of this transcription factor complex is modulated by growth factors, cytokines, and tumour promoters such as the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) (Ransone and Verma, 1990; Angel and Karin, 1991; Karin et al., 1997). The activated AP-1 dimer binds to specific DNA sequences in the regulatory regions of mitogen-responsive genes, so-called ‘TPA response elements’ (TRE) in the promoter regions of target genes (Angel et al., 1987; Lee et al., 1987), several of which are involved in cellular processes such as proliferation or tumour invasion in various tissues, including the human breast and endometrium (Bamberger et al., 1999, 2000a, 2001).
The purpose of the present study was, thus, to investigate systematically the expression of the AP-1 family of transcription factors in the human placenta. For this purpose, immunohistochemistry using specific antibodies against each of the seven transcription factors was employed to determine expression and tissue localization of the AP-1 proteins. Particular attention was given to the complex cellular structures of the placenta, and expression was assesed in the villous cyto- and syncytiotrophoblast and in all types of intermediate (extravillous) trophoblast, i.e. the part that actually invades the maternal tissue. In addition, western blot analysis was employed to investigate expression of the AP-1 factors in isolated villous cyto- and syncytiotrophoblast and intermediate (extravillous) trophoblast in primary culture.
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Materials and methods |
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Tissue collection
The study was approved by the Ethical Committee of the University of Hamburg. Placental tissue was selected following histological review from the files of the Department of Gynaecopathology, University Hospital Eppendorf, Hamburg, Germany, as well as from the Department of Obstetrics and Gynaecology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania. Only normal placentae were included. For immunohistochemistry, specimens which had been routinely fixed in 4% buffered formalin and embedded in paraffin were used. A total of 55 samples was analysed, including 33 first trimester, 10 second trimester and 12 third trimester placentae.
Immunohistochemistry
Serial sections of 4–6 µm were cut from the paraffin blocks and mounted on APES-coated slides, deparaffinized in xylene and rehydrated in graded alcohol to TBS (50 mmol/l Tris, 150 mmol/l NaCl, pH 7.4). The slides were microwaved for 5 x 2 min in 10 mmol/l citrate, pH 6.0. After cooling down for 20 min, the slides were washed in TBS, blocked for 30 min at room temperature with normal goat serum (Dako, Denmark), diluted 1:20 in TBS and incubated with the following anti-human AP-1 antibodies: c-Jun monoclonal antibody KM-1 (1:200), JunB polyclonal antibody No. 210 (1:100), JunD polyclonal antibody No. 329 (1:2000), c-Fos polyclonal antibody No. 4 (1:1000), FosB polyclonal antibody No. 102 (1: 200), Fra-1 polyclonal antibody No. R20 (1:400), and Fra-2 polyclonal antibody No. Q-20 (1:800) (all from Santa Cruz, Germany) for 24 h at room temperature. Non-immune murine or rabbit serum (Dako) was used for negative control. Slides were reacted with biotin-labelled corresponding secondary anti-mouse or anti-rabbit antibodies, incubated with preformed ABC-complex and detected with DAB-kit (all from Vectastain, Vector Laboratories, USA). Sections were counterstained with haematoxylin (Hemalaun Meyer; Merck, Germany), dehydrated and mounted (Eukitt; Labo-Med, Germany).
Histological and immunohistochemical evaluations were performed independently by two pathologists.
Isolation of trophoblast cells
Cultures of first trimester trophoblast populations were established and characterized as previously reported (Bamberger et al., 2000b). Briefly, 8–10 placentae (5–12 weeks) obtained after legal termination of pregnancy were washed in sterile phosphate-buffered saline (s-PBS), and areas rich in chorionic villi were selected and minced between scalpel blades and were subjected to three sequential 10 min treatments with 0.125% trypsin and 0.2 mg/ml DNAse I (Boehringer, Germany) in s-PBS containing 5 mmol/l MgCl2. Cells released from each 10 min step were pooled and filtered through two layers of muslin, resuspended in 70% Percoll (Pharmacia, Sweden) at a density of 2x105 cells/ml, and put under 20 ml of 25% Percoll. Ten millilitres of s-PBS was put on top of the 25% Percoll and a gradient was established by centrifuging for 20 min at 800 g. Cells from the middle band (density 1.048–1.062 g/ml) of the gradient were pooled, washed in s-PBS and seeded at a density of 1x106 cells/ml in keratinocyte growth medium (KGM) supplemented with 10% fetal calf serum (FCS). As previously described (Bamberger et al., 2000b), cells were identified as being trophoblast by immunocytochemical staining using monoclonal antibodies to cytokeratin (Dako-cytokeratin, MNF 116 and 35BH11, 1:100; Dako) as well as E-cadherin (HECD-1; Takara Shuzo Co., Japan). Intermediate (extravillous) trophoblast cells were further characterized and separated employing an in vitro matrigel invasion assay using transwells with a polycarbonate filter of 2.5 cm diameter and 8 µm pore size as described (Bamberger et al., 2000b).
Western blot analysis
Trophoblast cells were lysed in ice-cold sample buffer b1 [50 mmol/l Tris pH 6.8, 1% sodium dodecyl sulphate (SDS), and 10% sucrose] containing 20 µl protease inhibitor cocktail (Cat-No. P-8340, Sigma, Germany). Protein concentration was determined following standard protocols and using bovine serum albumin protein standards. For electrophoresis, samples were diluted with a 1:1 mixture of sample buffer b1 and b2 (containing 50 mmol/l Tris pH 6.8, 3% SDS, 10% sucrose, 10% ß-mercaptoethanol, and 0.01% Bromophenol Blue) to a final volume of 100 µl and a final protein concentration of 400 µg/ml. Equal amounts of protein (40 µg) of each sample were loaded per well and equal loading was verified by immunoblotting with actin antibodies (not shown). Electrophoresis was performed in a 10% polyacrylamide separating gel and a 3% stacking gel. Proteins were transferred to a polyvinyl difluoride membrane (Immobilon P; Millipore, Germany). Membranes were dried and submersed in 20% methanol in order to visualize homogeneity of protein lanes and to determine transfer. Membranes were then incubated overnight at 4°C in blocking solution (0.1 mol/l maleic acid, pH 7.5, 0.15 mol/l NaCl, 0.005% Thimomersal, and 1% blocking reagent; Boehringer, Germany) and incubated for 1 h at room temperature with the following antibodies (all from Santa Cruz, Germany) in the indicated dilutions in 9:1 TBST/blocking solution: c-Jun monoclonal antibody KM-1 (1:200), JunB polyclonal antibody No. 210 (1:100), JunD polyclonal antibody No. 329 (1:2000), c-Fos polyclonal antibody No. 4 (1:1000), FosB polyclonal antibody No. 102 (1: 200), Fra-1 polyclonal antibody No. R20 (1:400), and Fra-2 polyclonal antibody No. Q-20 (1:800). Blots were washed 3 x 10 min in TBST (20 mmol/l Tris–HCl, pH 7.6, 0.137 mol/l NaCl, 0.05% Tween 20) and incubated with the second antibody (peroxidase-conjugated anti-rabbit-IgG, 1:5000 in 9:1 TBST/blocking solution, and peroxidase-conjugated anti-mouse-IgG, 1:2000; both from Santa Cruz) for 1 h at room temperature. After extensive washing, the second antibody was visualized by chemiluminescence reagents (Super Signal Kit; Pierce, USA) and Hyperfilm ECL films (Amersham, Germany). Normal human endometrium (E) was used as a positive control.
In case of multiple bands, the specific AP-1 protein band was previously identified by apparent molecular weight relative to standard proteins (Rainbow Molecular Weight Markers; Amersham) and by preincubation of the primary antibodies with suitable blocking peptides (all from Santa Cruz) in blocking experiments (Bamberger et al., 1999).
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Representative photographs of the immunohistochemical localization of the AP-1 factors in the human placenta are presented in Figure 1A–I and Figure 2A–I. Figure 3 shows results of the western blot analysis of the expression of AP-1 proteins in primary placental culture of separated cytotrophoblast, syncytiotrophoblast and intermediate (extravillous) trophoblast cells. There were no substantial differences in the AP-1 expression pattern between different trimesters of pregnancy. However, the intermediate (extravillous) trophoblast can be most easily discriminated in second trimester placenta, which were therefore chosen for the figures.
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Representative immunohistochemical staining patterns of members of the Jun family are shown in Figure 1 (A–C, G: c-Jun; D–F, H: JunD; I: JunB). As can be observed, all Jun proteins are expressed in the nuclei of the intermediate (extravillous) trophoblast.
C-Jun (Figure 1A and B) appears to be more strongly expressed in the proximal intermediate (extravillous) trophoblast, whereas JunD (Figure 1D and E) is stronger in the deeper interstitial intermediate (extravillous) trophoblast.
As can be seen in Figure 1C, c-Jun is also expressed in the nuclei of some villous cytotrophoblast cells, thus being the only member of the AP-1 family to be expressed in these cells. Expression of c-Jun in villous cytotrophoblast (aside from its expression in intermediate trophoblast) was also observed in primary culture of villous cytotrophoblast cells analysed by western blot (shown in Figure 3).
Interestingly, c-Jun expression is also observed in the nuclei of fetal endothelial cells of villous vessels (Figure 1C), and in the nuclei of endovascular intermediate (extravillous) trophoblast, as shown in Figure 1G. While other AP-1 factors were also found to be expressed in the endovascular intermediate (extravillous) trophoblast, c-Jun expression was strongest in this cell type. Expression of c-Jun was also observed in the intermediate (extravillous) trophoblast of the chorion laeve (not shown).
JunD was found to be expressed in the nuclei of the intermediate (extravillous) trophoblast and, as already mentioned, appeared to be stronger in the deeper, interstitial zones of the intermediate (extravillous) trophoblast (Figure 1D and E).
Interestingly, JunD was also found to be expressed in nuclei of the villous syncytiotrophoblast (Figure 1F), thus being the only member of the AP-1 family to be expressed in these nuclei (very much the same as c-Jun being the only member of the AP-1 family to be expressed in the villous cytotrophoblast). Expression of JunD in syncytiotrophoblast (in addition to its expression in intermediate trophoblast) was also confirmed by western blot analysis of primary culture of villous syncytiotrophoblast (Figure 3).
JunB, the third member of the Jun family, was also found to be expressed in the nuclei of intermediate (extravillous) trophoblast in all locations (implantation site, endovascular and intermediate trophoblast of the chorion laeve), but the intensitiy of staining was not as strong as for c-Jun or JunD (Figure 1I). JunB was absent from villous cyto- and syncytiotrophoblast. Expression of JunB in primary placental culture (western blot analysis) is shown in Figure 3. As can be observed, the intensity of the bands is not as high as for c-Jun and Jun D, and expression is restricted to invasive trophoblast cells and is not found in villous cyto- or syncytiotrophoblast.
Representative immunohistochemical staining patterns for the members of the Fos family are presented in Figure 2 (A–E: c-Fos; F and G: Fra-2; H and I: FosB). As can be observed, all three factors are expressed in the nuclei of intermediate (extravillous) trophoblast, but are absent from villous cyto- and syncytiotrophoblast. c-Fos and Fra-2 showed the strongest expression levels, followed by FosB and Fra-1, the fourth member of this family, which was only very weakly expressed (not shown). Western blot analysis of placental cells in primary culture confirmed these findings (Figure 3), showing specific expression of the Fos-family members only in the intermediate (extravillous) trophoblast, and levels of expression which correlate with those observed in the immunohistochemical analysis.
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Discussion |
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TopABSTRACTIntroductionMaterials and methodsResultsDiscussionREFERENCES |
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The present study is to our knowledge the first systematic analysis of expression of the members of the AP-1 family of oncogenes/transcription factors in the human placenta. As shown by immunohistochemistry and western blot analysis of isolated placental cells in primary culture, all members of the AP-1 family are expressed in the intermediate (extravillous) trophoblast, most of them with strong levels of expression (c-Jun, JunD, c-Fos, FosB, and Fra-2), JunB with weaker expression level and Fra-1 with very weak expression. Two of the AP-1 factors (c-Jun and JunD) are also expressed in the villous trophoblast, with c-Jun being found in some nuclei of the cytotrophoblasts (immunohistochemically) and also in isolated cytotrophoblast cells in primary culture (western blot analysis), whereas JunD is found in syncytiotrophoblast nuclei (immunohistochemically) and in fused syncytiotrophoblast in primary culture (western blot analysis). This expression pattern indicates that, in the process of differentiation, migration and invasion of the intermediate (extravillous) trophoblast, a switch in transcription factor expression takes place which might be partly responsible for differences in expression of several markers between the proximal and interstitial intermediate (extravillous) trophoblast.
In vitro studies have shown that Jun homodimers have less DNA binding activity than do Jun/Fos heterodimers (Ryseck and Bravo, 1991). Fos/Jun heterodimers are more stable and have a higher affinity to AP-1 or AP-1-like elements compared with Jun homodimers, with the most stable complexes being formed by Jun proteins and FosB (Ryseck and Bravo, 1991). As DNA binding is necessary for transactivation, the expression of different proteins of the Fos family is crucial for full activation of downstream genes regulated by AP-1. Therefore, the invasive cell population of the human placenta, i.e. the intermediate (extravillous) trophoblast, fulfils the prerequisite for transactivation of AP-1 target genes, since it expresses all members of both the Jun and the Fos family.
The human trophoblast is characterized by a tightly controlled programme of cell proliferation, differentiation, invasion, angiogenesis, and apoptosis. Transcription factors belonging to the AP-1 family have been shown to be essential players in these processes in other tissues, especially in tumours derived thereof (Ozanne et al., 2000; Tulchinsky, 2000; Jochum et al., 2001; Shaulian and Karin, 2001, 2002). Expression in the human placenta has so far only been shown at the mRNA level and without analysing the expression pattern in the different subpopulations of the trophoblast (Dungy et al., 1991). This previous study points to a change from predominant c-Jun to Jun B expression as pregnancy advances. Since c-Jun is considered a major stimulator of proliferation whereas Jun B inhibits this process (Shaulian and Karin, 2002), this switch may be one of the placenta-specific mechanisms preventing tumour-like, i.e. uninhibited, expansion of the trophoblast. In animals, knockout experiments have revealed some non-redundant functions of most of the AP-1 family members. As far as the utero-placental system is concerned, these experiments pointed to a specific role for JunB and Fra-1. Inactivation of each of these genes led to severe growth retardation and early fetal death due to impaired vascularization of the decidua (Schorpp-Kistner et al., 1999; Schreiber et al., 2000).
Our data indicate a specific role of AP-1 proteins in the process of invasion of maternal tissue by the trophoblast. Not only are they predominantly expressed in the invasive subpopulation of the trophoblast, i.e. the intermediate (extravillous) trophoblast, but within this subpopulation, c-Jun and JunD particularly display a highly interesting expression pattern: while c-Jun is more strongly expressed in the proximal intermediate (extravillous) trophoblast, JunD staining is stronger in the deeper interstitial layers of the intermediate (extravillous) trophoblast. This indicates that there might be a spatial transcription factor switch, concerning at least these two members of the AP-1 family during the development and migration/invasion of the intermediate (extravillous) trophoblast.
Differences in expression of several other factors have been described during the progression from proximal to a deeper interstitial part of the intermediate (extravillous) trophoblast (Frank and Kaufmann, 2000). Some of these factors might be of interest when trying to interpret the role of the observed differences in expression of c-Jun and JunD. One such category is that of growth factor receptors, particularly the receptor for EGF/TNF-
encoded by c-erbB1, which is expressed in the proximal layer of intermediate (extravillous) trophoblast cell columns, while c-erbB2 shows a reciprocal expression pattern, being positive on cells of more differentiated and distal invasive stages (Aboagye-Mathiesen et al., 1997; Morrish et al., 1998). Also, the receptor for CSF-1, encoded by c-fms, is strongly expressed in early invasive stages and is weaker during deeper invasion (Aboagye-Mathiesen et al., 1997; Morrish et al., 1998). It is conceivable that these receptors, being activated by mitogens, in turn activate kinase cascades followed by activation of transcription factors of the AP-1 family and that, at this point, differences in expression of these factors might be of importance in generating different expression of target genes.
Among the numerous AP-1 target genes, very few have been analysed within trophoblast tissues. The matrix metalloproteinases (MMP) are essential for the degradation of extracellular matrix and thus for tissue invasion. Several of these MMP, particularly MMP-2 and MMP-9, have been shown to be predominantly expressed in the intermediate (extravillous) trophoblast (Huppertz et al., 1998; Bischof et al., 2002). Moreover, they represent classic AP-1 target genes having TRE (trx-G response elements) in their promoter regions (Bischof et al., 2002). Therefore, the cell type- and time-dependent expression of AP-1 proteins in this tissue could be an integral part of the complex network governing invasion of the maternal tissue by the trophoblast. The human placental lactogen (hPL) gene is another target gene for AP-1 transcription factors (Peters et al., 2000), indicating that these factors could also be involved in the regulation of placental hormone production. Finally, the AP-1-dependent gene encoding 15-hydroxyprostaglandin dehydrogenase is also preferentially expressed in the proliferating and invading cells of the human trophoblast (Cheung et al., 1992; Greenland et al., 2000). Since it degrades labour-inducing prostaglandins, this enzyme is considered to be essential for preventing preterm labour (van Meir et al., 1997). In addition to being involved in the regulation of invasion and hormone production by the human trophoblast, AP-1 proteins could also participate in the timing of the onset of labour.
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Acknowledgement |
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We gratefully acknowledge the help of J.Koppelmeyer with the graphical work.
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Submitted on September 30, 2003; accepted on October 7, 2003.
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