Expression and Localization of the Transcription Factor JunD in the Duct System of Mouse Submandibular Gland
Department of Histology and Embryology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
Correspondence to: Shoichi Iseki, MD, PhD, Dept. of Histology and Embryology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan. E-mail: siseki{at}med.kanazawa-u.ac.jp
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Summary |
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Key Words: AP-1 JunD immunohistochemistry submandibular gland duct mouse
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Introduction |
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In contrast, development of the mature duct system, which is represented by the differentiation of granular convoluted tubule (GCT) cells from striated duct (SD) cells, occurs during puberty under the control of hormonal factors such as androgens, thyroid hormones, and adrenocortical hormones (Chretien 1977; Pinkstaff 1980
; Gresik 1994
). In particular, androgens are considered the primary factor of GCT differentiation because in the mouse there is a marked sexual dimorphism in the development of GCT that proceeds around 35 weeks postpartum. Castration of adult male mice causes marked regression of GCT owing to conversion of GCT cells to SD cells, whereas administration of androgens to castrated male or normal female mice readily causes the opposite phenomenon (Caramia 1966b
; Chretien 1977
). GCT cells are characterized by large secretory granules that contain a variety of biologically active polypeptides, including nerve growth factor (NGF), epidermal growth factor (EGF), renin, and kallikreins (Barka 1980
; Gresik 1994
).
The androgens exert their biological functions by binding to the androgen receptor (AR), a member of the nuclear receptors that is believed to act as a transcription factor in itself by binding to androgen response element (ARE) upstream of the androgen-regulated genes (Zhou et al. 1994; Chang et al. 1995
; Brinkmann et al. 1999
). AR is expressed in both acinar and duct cells of the rodent submandibular gland (Morrell et al. 1987
; Zhuang et al. 1996
). However, little is known about the mechanisms by which the androgen/AR system causes differentiation of GCT, including the gene product that is induced by androgen and plays a crucial role in GCT cell differentiation.
Recently, we found in the rat submandibular gland that CREB is expressed abundantly in the nuclei of intercalated duct (ID) cells and distal SD cells for 35 weeks postpartum but is no longer expressed in differentiated GCT cells (Amano and Iseki 1998; Kim et al. 2001
). Administration of testosterone to immature or hypophysectomized rats caused a temporary increase in the number of CREB-positive SD cells before their differentiation to GCT cells. Furthermore, inhibition of CREB synthesis by the antisense oligonucleotide led to suppression of GCT cell differentiation. These results suggested the existence of cross-talk between the cAMP/PKA and the androgen/AR signaling pathways in the mechanisms of androgen-dependent GCT differentiation.
Here we examined the expression of another transcription factor, activator protein-1 (AP-1), in the mouse submandibular gland. The AP-1 family is a complex composed of the Jun family (c-Jun, JunB, and JunD) and the Fos family (c-Fos, FosB, Fra1, and Fra2), the proto-oncogene-encoded nuclear proteins. The Jun family members form homo- or heterodimers among themselves or heterodimers with the Fos family members and bind to the AP-1 consensus DNA sequence located in the promoter region of a variety of target genes (Vogt and Bos 1990; Angel and Karin 1991
). The activity of AP-1 in transactivating the expression of target genes is regulated at both the transcriptional and the post-translational level. The transcription of c-Jun is positively regulated by binding of c-Jun homodimers to an AP-1 site located in the promoter region of c-Jun gene itself, whereas the transcription of c-Fos is induced by a variety of factors such as serum, hormones, growth factors, and cytokines, through their cognate signaling pathways and cis-acting elements in the c-Fos promoter. On the other hand, the post-translational activation of AP-1 is represented by phosphorylation and/or dephosphorylation of c-Jun protein, which is also regulated by a variety of signaling pathways (Angel and Karin 1991
; Karin 1995
).
AP-1 has been implicated in the regulation of cell proliferation, differentiation, apoptosis, and transformation in many in vitro and in vivo systems. In the mouse submandibular gland, stimulation of the ß-adrenergic receptor by isoproterenol causes a rapid, transient induction of c-Fos expression in both acinar and duct cells, although the biological significance of this phenomenon has not been clarified (Barka et al. 1986). In this study, by use of immunochemical and immunohistochemical methods, we demonstrate that many AP-1 family members, primarily JunD, are expressed exclusively in the duct system of mouse submandibular gland, and that JunD expression and localization are regulated in association with the androgen-dependent duct cell differentiation.
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Materials and Methods |
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Western Blotting Analysis
Rabbit polyclonal IgG antibodies against the synthetic peptides of the Jun family members (c-Jun, JunB, and JunD), Fos family members (c-Fos, FosB, Fra1, and Fra2), mouse NGF, and actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). The frozen mouse submandibular glands were homogenized in a lysis buffer composed of 1% Nonidet P40, 0.5% sodium deoxycholate, 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, and the proteinase inhibitor cocktail (Roche; Mannheim, Germany). After centrifugation at 3000 rpm, the supernatants were examined for the protein concentration using a BCA protein assay kit (Pierce; Rockford, IL) and used as cell lysates. The cell lysates at 20 µg protein/lane were separated by electrophoresis in a 15% polyacrylamide gel in the presence of 0.1% SDS and then transferred to PVDF membranes (BioRad Laboratories; Hercules, CA). After treatment with 4% non-fat skimmed milk in PBS plus 0.01% Tween-20, the membranes were incubated with the rabbit antibodies against the primary antibodies at 0.05 µg/ml for 1 hr at room temperature (RT). This concentration of the antibodies was determined in preliminary experiments to give the maximal immunoreactions for all antigens. After washing with PBS plus 0.01% Tween-20, the membranes were incubated with horseradish peroxidase-conjugated anti-rabbit IgG antibody (DAKO; Glostrup, Denmark) at 1:3000 dilution for 1 hr. The immunoreactions were detected with X-ray films (Kodak X-OMAT AR) after treatment of the membranes with the chemiluminescence kit ECL-plus (Amersham Pharmacia Biotech; Uppsala, Sweden). For a negative control, the antibodies were absorbed with a tenfold amount of the peptide antigen used for immunization (Santa Cruz Biotechnology) for 1 hr at 4C before use.
Immunodot-blot Assay
Five µl of the cell lysates of submandibular glands from three mice in each experimental condition were serially diluted, spotted in duplicate onto methanol-activated PVDF membranes, and dried. The blots were then immunostained with anti-JunD antibody and visualized using chemiluminescence in the same way as for Western blotting. The developed X-ray films were scanned with an Epson GT-9800F scanner and the densitometric analysis of blots was performed with Image Gage V3.41 software (Fuji Photo Film; Tokyo, Japan). Within the dilutions of lysate showing proportional increase in optical density, the relative immunoreactivity of each sample was determined in terms of the mean optical density of duplicate blots. The values were expressed as the mean ± SD of three samples, and the difference between two values with p<0.05 was considered significant on Student's t-test.
Immunohistochemistry
The fixed submandibular glands were dehydrated with a graded ethanol series, cleared with xylene, and embedded in paraffin. Five-mm sections were cut from the paraffin blocks and mounted on gelatin-coated glass slides. The sections were treated successively with 0.3% Tween-20 in PBS for 1 hr for cell permeabilization, 0.3% H2O2 in methanol for 10 min to inhibit intrinsic peroxidase activity, and 3% normal swine serum for 30 min to prevent nonspecific antibody binding. They were then incubated overnight at RT with rabbit anti-JunD antibody or rabbit anti-NGF antibody at a concentration of 0.5 µg/ml in PBS. To confirm the specificity of immunoreactions, the antibodies were absorbed with a tenfold amount of the corresponding peptide antigen for 1 hr at 4C before use. After washing, the sites of immunoreactions were visualized by incubating the sections successively with biotinylated anti-rabbit IgG antibody (Vector Laboratories; Burlingame, CA) at 1:200 dilution for 1 hr, horseradish peroxidase-conjugated streptavidin (DAKO) at 1:300 dilution for 1 hr, and 0.01% diaminobenzidine tetrahydrochloride in the presence of 0.02% H2O2 in 50 mM Tris-HCl, pH 7.5, for about 10 min. The sections were observed under an Olympus BX50 microscope connected to a CCD video camera system. At 480-fold magnification, three fields were selected randomly from each of the sections obtained from three animals at each experimental condition. The percentage of JunD-immunopositive cell nuclei to the total cell nuclei in the duct system (ID, SD, GCT, and excretory ducts), defined as the ratio of immunopositive nuclei, was calculated for each field and expressed as the mean ± SD of nine fields. The difference between two values with p<0.05 was considered significant on Student's t-test. In one experiment, fluorescent double immunostaining for JunD and NGF was performed. The sections were incubated with a mixture of rabbit anti-JunD antibody (4 µg/ml) and sheep anti-NGF antibody (1 µg/ml; Chemicon, Temecula, CA) overnight at RT. After washing, the sections were incubated with a mixture of Cy3-labeled anti-rabbit IgG (6.5 µg/ml; Jackson ImmunoResearch Laboratories, West Grove, PA) and Cy2-labeled anti-goat IgG (32.5 µg/ml; Jackson ImmunoResearch Laboratories) for 1 hr. They were then mounted in glycerol and observed with an Olympus BX50/BX-FLA fluorescent microscope using green emission for Cy3 and blue emission for Cy2.
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Results |
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Discussion |
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During postnatal development of the rodent submandibular gland, it is generally accepted that SD cells differentiate to GCT cells in an androgen-dependent manner (Cutler and Chaudhry 1975; Gresik and MacRae 1975
; Srinivasan and Chang 1975
). GCT cells first occur in the distal portions of SD by 2 W postpartum and show a much more rapid increase in numbers in the male than in the female at around 35 W in mice and 48 W in rats. ID cells in the developing gland are considered to serve as the stem cells that proliferate and give rise to both SD and acinar cells. On the other hand, in adult male mouse gland, the number of SD cells is very small, and 70% of the renewal of the GCT cell population is estimated to occur by self-proliferation. The other 30% is believed to occur by the differentiation of ID and SGD cells, which have high proliferating activity, into GCT cells (Denny et al. 1993
). ID cells in adult glands are considered to give rise exclusively to GCT cells and not to acinar cells. These facts, together with the morphological features of the duct cell populations, suggest that SGD cells are the intermediate between ID and GCT cells and there is a cell lineage that originates in ID and sequentially differentiates to GCT cells (Denny et al. 1999
). In this regard, the higher proportion of SGD cells in the female gland relative to the male gland may be the result of a prolonged or abortive differentiation of ID cells into GCT cells, due to low plasma androgen levels. The present study demonstrated that nuclear JunD immunoreactivity is present in most ID and SD cells in the early postnatal weeks, whereas in adults it is present in ID and SGD cells but is absent in GCT cells and most SD cells. These results suggest that JunD is required in the cells on the course of their differentiation to GCT cells but is no longer required in differentiated GCT cells.
In the present study, administration of testosterone to female mice caused almost complete conversion of SD cells to GCT cells in 48 hr, in agreement with the past literature. The temporary rise in JunD immunoreactivity at 624 hr was associated with the temporary appearance of nuclear immunoreactivity in SD cells. This newly induced immunoreactivity disappeared as those SD cells converted to GCT cells, a phenomenon confirmed by the double immunostaining showing the lack of co-existence of nuclear JunD and cytoplasmic NGF in the same cell. We hypothesize that adult female SD cells, unlike ID and SGD cells, normally do not undergo differentiation to GCT cells but are induced by testosterone to enter this process. The expression of nuclear JunD is critical for this process but is no longer required in differentiated GCT cells. In this context, the quantitative gap between the two parameters of JunD expression obtained in the male and female glands is noteworthy. In adults, the ratio of female to male glands was 12-fold in terms of the relative immunoreactivity quantified by immunoblotting, whereas it was only 1.7-fold in terms of the ratio of immunopositive nuclei. This may be interpreted by assuming that the female SD cells produce a considerable amount of immunoreactive JunD but that this JunD is not localized in the nuclei for some reason, e.g., it may be inactive and not bound to the AP-1 element on DNA. Testosterone might cause activation of JunD in SD cells so that it translocates to the nuclei and binds to DNA. However, the possibility cannot be ruled out that the quantitative difference in the two parameters is due to a difference in the sensitivity of the two techniques of JunD detection. Further study employing molecular biological techniques is required to clarify this issue.
JunD is expressed much more abundantly than c-Jun and JunB in quiescent 3T3 cells and is constitutively expressed in high levels in a variety of mouse tissues (Hirai et al. 1989; Ryder et al. 1989
). In comparison with c-Jun and JunB expression, which is rapidly and transiently induced by such agents as serum, growth factors, and phorbol ester, JunD expression is believed to be relatively constant in amount and unresponsive to extracellular signals (De León et al. 1995
). Nevertheless, there is a growing body of evidence for the involvement of JunD as the main component of AP-1 in many biological phenomena, including growth factor-induced proliferation of lung fibroblasts (Eickelberg et al. 1999
), gonadotropin-induced luteinization of ovarian granulosa cells (Sharma and Richards 2000
), decidual formation by endometrial stromal cells (Watanabe et al. 2001
), and transformation of hepatic stellate cells to a myofibroblast-like phenotype (Smart et al. 2001
). The present study has pointed to differentiation of the duct system in the mouse submandibular gland as a candidate for a JunD-dependent phenomenon.
The activity of the Jun family members is post-translationally regulated by their phosphorylation states. Two types of phosphorylation sites exist in the Jun proteins, one adjacent to the DNA-binding domain and the other in the N-terminal transactivating domain (Angel and Karin 1991; Karin 1995
). Phosphorylation of the former site negatively regulates Jun activity, and protein kinase C causes dephosphorylation of this site through either activation of a phosphatase or inhibition of a protein kinase, and thereby increases the DNA-binding activity of AP-1 (Boyle et al. 1991
; Nikolakaki et al. 1993
). Phosphorylation of the latter site, in contrast, positively regulates Jun activity, and activation of Jun N-terminal kinase (JNK) through Ras-MAP kinase pathways causes phosphorylation of this site and thereby increases the transactivating potential of AP-1 (Pulverer et al. 1991
; Karin 1995
). On the other hand, the promoter region of Jun genes contains not only an AP-1 site but also multiple cis-acting elements that differ among the three members of Jun family, through which expression of the Jun proteins is potentially regulated at the transcriptional level (de Groot et al. 1991a
c). For the JunD promoter, these elements include a CRE, SP-1 binding site, an octamer motif, a CAAT box, a Zif268-binding site, a TATA box, and a variant AP-1 site, of which the octamer motif is unique to the JunD promoter and is postulated to be responsible for the constitutive transcription of JunD protein (de Groot et al. 1991c
). The present pattern of JunD expression in the submandibular gland duct system consists of constitutive expression in ID and SGD cells, permanent downregulation in GCT cells, and temporary upregulation in SD cells stimulated with testosterone. Which of the regulatory mechanisms in JunD expression accounts for this pattern remains to be revealed.
The present study has also suggested a cross-talk between the androgen/AR system and the AP-1 system. Androgens belong to the family of hydrophobic ligands whose biological effects are mediated by their cognate nuclear receptors (Laudet et al. 1992), which serve as transcription factors themselves by binding to their cognate hormone-response elements in the promoter region of target genes (Nelson et al. 1999
). Thus far, estrogen has been shown to increase c-jun expression in the uterus (Weisz et al. 1990
; Chiappetta et al. 1992
), which can be explained by transactivation by the estrogen receptor through an estrogen response element-like consensus sequence in the c-Jun gene (Hyder et al. 1995
). In the present phenomena, however, AR-mediated transactivation of JunD expression through ARE is unlikely because no ARE-like consensus sequence has been found in the JunD gene. The present effects of androgen on JunD expression in the submandibular duct system, i.e., upregulation in SD cells and downregulation in GCT cells, can be exerted either by the ligand androgen, AR, or the early responsive products of androgen-regulated genes, at the level of either transcription of JunD or post-translational activation of JunD, and should be clarified in the future study. In addition, the target gene(s) activated by JunD that is responsible for the androgen-dependent differentiation of GCT cells, as well as the role of the Jun and Fos family members other than JunD in the androgen effects, remain to be investigated.
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Acknowledgments |
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We wish to thank Mr S. Yamazaki and Ms Y. Akabori for their technical and secretarial assistance.
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Footnotes |
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