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PubMed1984

Glucocorticoid-dependent uteroglobin synthesis and uteroglobulin mRNA levels in rabbit lung explants cultured in vitro.

In rabbit lung explants cultured in vitro in a synthetic medium, the synthesis of the protein uteroglobin decayed progressively becoming virtually undetectable between 24-48 h of culture. Addition of glucocorticoids to the medium maintained the synthesis of uteroglobin. This glucocorticoid effect was dose-dependent with optima at about 0.1 microM and 1 microM for dexamethasone and cortisol respectively. Estradiol, progesterone, triiodothyronine, insulin or 10% calf serum added to the medium were ineffective in maintaining uteroglobin synthesis. Actinomycin D (10 micrograms/ml) added to the medium inhibited the effect of cortisol on uteroglobin synthesis. After 24 h of culture, both the relative levels of uteroglobin mRNA, measured by molecular hybridization, and uteroglobin synthesis were correlatively higher (up to 10-fold) in glucocorticoid-treated than in control explants.

Animals↗

PubMed1991

Expression of the uteroglobin promoter in epithelial cell lines from endometrium.

To understand the molecular mechanism of endometrial differentiation we have initiated an analysis of the uteroglobin promoter. Uteroglobin is normally expressed in endometrial tissues under the control of ovarian hormones. In gene transfer experiments with the Ishikawa cell line, derived from a human endometrial adenocarcinoma, we have identified several regions in the promoter of the uteroglobin gene that are responsible for its endometrium-specific expression. To evaluate the generality of these findings, we have begun cloning the promoter regions of potential endometrial markers, including the rat, mouse, and human uteroglobin gene. In the rat, expression of the uteroglobin-like gene, CC10, is dominant in the lung but is also observed in the endometrium of progesterone treated animals. A comparison of the 5'-flanking sequence of the rat and rabbit uteroglobin gene resulted in the detection of similarities and differences that could explain their differential expression in vivo. To substantiate these findings we have established several cell lines from rat endometrium using murine retroviral vectors containing a positive selection marker and various viral oncogenes, such as SV40 large T antigen, adenovirus E1A, and Ha-ras. Cell lines immortalized by SV40 T-antigen were subsequently transformed with the Ha-ras oncogene. Several cell lines exhibit properties of epithelial endometrial cells. Two cell lines generated with a temperature sensitive mutant of the SV40 large T-antigen grow as transformed cells at the permissive temperature, but differentiate upon shifting to the non-permissive temperature. These rat endometrial cell lines should be useful for the analysis of endometrium-specific gene expression and as model systems for endometrial carcinoma.

Animals↗

PubMed1990

High level bacterial expression of uteroglobin, a dimeric eukaryotic protein with two interchain disulfide bridges, in its natural quaternary structure.

Bacterial expression of eukaryotic proteins is a tool of ever-increasing importance in biochemistry and molecular biology. However, the majority of the recombinant eukaryotic proteins that have been expressed in bacteria are produced as fusion proteins and not in their native conformation. In particular, correct formation of quaternary structures by recombinant proteins in bacterial hosts has been reported very rarely. To our knowledge, correct intracellular formation of multimeric structures containing more than one interchain disulfide bridge has not been reported so far. We have constructed three plasmids which are able to direct expression of recombinant rabbit uteroglobin, a homodimeric protein with two interchain disulfide bridges, in Escherichia coli. Among these, the plasmid pLE103-1, in which the expression of recombinant uteroglobin is controlled by a bacteriophage T7 late promoter, is by far the most efficient. With pLE103-1, recombinant uteroglobin production reached about 10% of total bacterial soluble proteins. This protein accumulated in bacterial cells in dimeric form, as it is naturally found in the rabbit uterus. Recombinant uteroglobin was purified to near-homogeneity and its NH2-terminal amino acid sequence was confirmed to be identical to that of its natural counterpart, except for 2 Ala residues the codons for which were added during the plasmid construction. This protein was found to be as active a phospholipase A2 inhibitor as natural uteroglobin on a molar basis. To our knowledge, this is the first report of high level bacterial expression of a full length eukaryotic homodimeric protein with two interchain disulfide bridges in its natural, biologically active form. The plasmid pLE103-1 may be useful to explore structure-function relationships of rabbit uteroglobin. In addition, this plasmid may be useful in obtaining high level bacterial expression of other eukaryotic proteins with quaternary structure, as well as for other general applications requiring efficient bacterial expression of cDNAs.

Animals↗

PubMed1975

Uteroglobin-like antigen in the male genital tract secretions.

The secretion of the rabbit seminal vesicle has been investigated by morphological and biochemical means. Apical regions of seminal vesicle epithelial cells show highly active protein synthesizing and releasing organells. The secretory proteins released are analysed by disc-electrophoresis and three different immunological procedures. There is evidence for the presence of an uteroglobin-like antigen in seminal vesicle secretion. Comparison with seminal plasma indicated that the uteroglobin-like protein is also present in this fluid. The immunological and electrophoretical identity of rabbit uteroglobin, obtained from the uterus, with "male uteroglobin" is obvious, but molecular-biochemical and biological identity awaits further clarification. The demonstration of uteroglobin-like antigen in the male as in the female points towards new aspects in reproductive and contraceptive research.

Animals↗

PubMed1981

5 alpha-Dihydrotestosterone-induced uteroglobin synthesis in rabbit uterus is not inhibited by antiandrogen administration but is prevented by estradiol.

The physiological androgen, 5 alpha-dihydrotestosterone (DHT), enhances a progesterone-regulated protein (uteroglobin) synthesis in the rabbit uterus. In order to clarify the induction mechanism(s), rabbits were treated for 5 days with DHT alone or concomitantly with a nonsteroidal antiandrogen, RU 23908, or with different doses of estradiol. Uteroglobin content was measured in the uterine fluid by radioimmunoassay and uteroglobin mRNA activity in uterine tissues using cell-free translation in vitro. Uteroglobin induction elicited by DHT was inhibited by a small dose of estradiol, but not by antiandrogen. These results support the idea tha androgens bring about their action on uteroglobin synthesis via a mechanism involving uterine progesterone receptor.

Androgen Antagonists↗

PubMed1987

Inhibition of thrombin-induced platelet aggregation by uteroglobin.

Uteroglobin, a steroid-dependent, small molecular weight (15K) protein in the rabbit, inhibited thrombin-induced aggregation of both rabbit and human gel-filtered platelets (GFP). GFP aggregation by arachidonic acid was not affected by uteroglobin. There were no effects of uteroglobin on thrombin-induced clotting of plasma or purified fibrinogen, or inhibition of thrombin by antithrombin III. Additionally, preliminary results suggest that uteroglobin does not interfere with binding of thrombin to platelets. We suggest that inhibition of platelet aggregation by uteroglobin may function in preventing thrombosis and ensuring free flow of blood through the microvasculature of the uterus and the placenta and may induce some of the antimotility effects of progesterone on the uterus.

Animals↗

PubMed1993

Uteroglobin, an apically secreted protein of the uterine epithelium, is secreted non-polarized form MDCK cells and mainly basolaterally from Caco-2 cells.

A complete cDNA encoding rabbit uteroglobin was constructed and expressed in MDCK and Caco-2 cells. The MDCK cells secrete uteroglobin in approximately equal amounts to the apical and the basolateral side, whereas the Caco-2 cells secrete uteroglobin mainly to the basolateral side. Both MDCK and Caco-2 cells thus secrete uteroglobin in a non-sorted manner. It has, however, previously been shown that uteroglobin is secreted exclusively at the apical membrane in primary cell culture of endometrial epithelial cells [S.K. Mani et al. (1991) Endocrinology 128, 1563-1573]. This suggests that either the endometrial epithelium has an apical default pathway or recognises a sorting signal not recognised by MDCK cells and Caco-2 cells. Our data thus show that a soluble molecule can be secreted at the apical, the basolateral or both membranes depending on the cell type.

Animals↗

PubMed1981

Hormonal control of uteroglobin secretion and preuteroglobin mRNA content in rabbit endometrium.

The cellular content of preuteroglobin mRNA in endometrium was measured by molecular hybridization to preuteroglobin cDNA, and compared with uteroglobin content in the uterine secretion as determined by radioimmunoassay. The following results were obtained. (1) A single injection of either estradiol or progesterone leads to a rapid accumulation of preuteroglobin mRNA in the endometrium, but has no effect on the cellular content of preuteroglobin mRNA in the lung. (2) The effect of progesterone on uteroglobin on secretion parallels its influence on preuteroglobin mRNA levels, but estradiol has a more pronounced effect on the mRNA content than on uteroglobin secretion. (3) 5 days after priming with estradiol, a single injection of progesterone leads to the accumulation of preuteroglobin mRNA sequences without measurable lag phase, whereas a lag period is found if progesterone is administered earlier after estradiol treatment. (4) In the endometrium of pseudopregnant rabbits there are around 10 000 molecules of preuteroglobin mRNA per epithelial cell as compared with 300 in control estrous rabbits, and 1000-2000 in animals treated with estradiol alone. (5) Following maximal induction, the apparent half-life of uteroglobin and its mRNA are inversely influenced by estrogens: estradiol accelerates the disappearance of uteroglobin from the uterine secretion, and retards the decay of preuteroglobin mRNA sequences in endometrium.

Animals↗

PubMed2004

Gene profiling reveals increased expression of uteroglobin and other anti-inflammatory genes in glucocorticoid-treated nasal polyps.

BACKGROUND: Treatment with local glucocorticoids (GCs) decreases symptoms and the size of nasal polyps. This might depend on the downregulation of proinflammatory genes, as well as the upregulation of anti-inflammatory genes. OBJECTIVE: We sought to identify GC-regulated anti-inflammatory genes in nasal polyps. METHODS: Affymetrix DNA microarrays were used to analyze the expression of 22,283 genes in 4 nasal polyps before and after local treatment with fluticasone (400 microg/d). Expression of uteroglobin and mammaglobin B was analyzed with real-time PCR in 6 nasal polyps and in nasal biopsy specimens from 6 healthy control subjects. RESULTS: Two hundred three genes had changed in expression in treated polyps, and 139 had known functions: 54 genes were downregulated, and 85 were upregulated. Genes associated with inflammation constituted the largest single functional group. These genes affected key steps in inflammation (eg, immunoglobulin production; antigen processing and presentation; and the chemoattraction and activation of granulocytes, T cells, and B cells). Several proinflammatory genes were downregulated. In contrast, some anti-inflammatory genes were upregulated. The gene that increased most in terms of expression was uteroglobin. This was confirmed with real-time PCR. By contrast, expression of uteroglobin was lower in untreated polyps than in healthy nasal mucosa. Immunohistochemical investigation showed staining of uteroglobin in the epithelium and in seromucous glands in control subjects and in nasal polyps. CONCLUSION: Upregulation of anti-inflammatory genes, such as uteroglobin, might contribute to the effects of local treatment with GCs in nasal polyps.

Adult↗

PubMed1985

Glucocorticoids induce the expression of the uteroglobin gene in rabbit foetal lung explants cultured in vitro.

In 27-day-old rabbit foetal lung explants cultured in vitro, the synthesis of the protein uteroglobin decreased progressively during several days of culture. Addition of glucocorticoids to the medium progressively induced the synthesis of uteroglobin in a dose-dependent manner without affecting the synthesis of total proteins. The glucocorticoid-mediated induction of uteroglobin appears mainly due to increased amounts of uteroglobin mRNA and seems to be independent of simultaneous cell proliferation, suggesting a glucocorticoid-triggered differentiation of pre-existing cells. The results suggest a major role of glucocorticoids in the developmental regulation of the uteroglobin gene in the lung.

Animals↗

PubMed1988

Testosterone induces the expression of the uteroglobin gene in rabbit epididymis.

Uteroglobin was characterized in the rabbit epididymis by radioimmunoassay and electrophoretic determinations, as well as by analysis of its mRNA by means of 'Northern blot' and nuclease-S1 mapping. Treatment of sexually immature rabbits with testosterone during 5 days increased up to 8-fold the concentrations of both uteroglobin and its mRNA in the epididymis. The amounts of beta-tubulin mRNA, measured as reference, remained unchanged after the hormonal treatment. The synthesis of uteroglobin occurred mainly in the middle region of the epididymis, progressively decreasing toward the distal part of the organ. Uteroglobin was not detected in the testis by radioimmunoassay. The results are discussed in relation to a possible role of uteroglobin in the reproductive functions.

Animals↗

PubMed2000

Association of a uteroglobin polymorphism with rate of progression in patients with IgA nephropathy.

Uteroglobin gene-disrupted mice develop a nephritis very similar to immunoglobulin A (IgA) nephropathy. Megsin codes for a protein overexpressed in mesangium in patients with IgA nephropathy. Both are candidate genes that might have variants associated with an accelerated progression in patients with IgA nephropathy. We performed an association study of patients with IgA nephropathy and matching control subjects to test whether the G38A polymorphism in the uteroglobin gene, the C2093T polymorphism in the megsin gene, or the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism is associated with IgA nephropathy or rate of disease progression in patients with IgA nephropathy. Of 110 patients with IgA nephropathy, 87 patients were followed up for at least 3 years for the progression study. We also studied 104 healthy volunteers. The uteroglobin, megsin, and ACE polymorphisms were not distributed differently in the 110 patients with IgA nephropathy compared with healthy controls; Hardy-Weinberg equilibrium criteria were fulfilled. The GG genotype of the G38A uteroglobin polymorphism was more common in patients with progression (odds ratio [OR], 3.5; P< 0.006) than the AG+AA genotypes. The G allele was also more common (OR, 2.6; P< 0.009) in patients with versus without progression. The 1/serum creatinine over time plot (in deciliters per milligram per day) was sevenfold steeper in GG patients than the other two genotypes (P = 0.08). No significant associations with disease progression were found for the other gene polymorphisms, and a multivariate analysis showed no interactions. We suggest the hypothesis that the uteroglobin gene contains variant(s) with a bearing on progression rate in patients with IgA nephropathy.

Adult↗

PubMed1983

The uteroglobin gene region: hormonal regulation, repetitive elements and complete nucleotide sequence of the gene.

Differential uteroglobin induction represents an appropriate model for the molecular analysis of the mechanism by which steroid hormones control gene expression in mammals. We have analyzed the structure and hormonal regulation of a 35 Kb region of genomic DNA in which the uteroglobin gene is located. The complete sequence of 3,700 nucleotides including the uteroglobin gene and its flanking regions has been determined, and the limits of the gene established by S1 nuclease mapping. Several regions containing repeated sequences were mapped by blot hybridization, one of which is located within the large intron in the uteroglobin gene. Analysis of the RNAs extracted from endometrium, lung and liver, after treatment with estrogen and/or progesterone shows that within the 35 Kb region, the uteroglobin gene is the only DNA segment whose transcription into stable RNA is induced by progesterone.

Amino Acid Sequence↗

PubMed1995

Progesterone binding to uteroglobin: two alternative orientations of the ligand.

Progesterone binding to a homodimer of uteroglobin takes place in a hydrophobic cavity formed by the two subunits. Previous mutational analyses have shown that the tyrosine (21 and 21') and threonine (60 and 60') residues of the uteroglobin dimer are directly involved in progesterone binding. To analyze the contribution of each of the two tyrosines and threonines in the dimer, we have constructed a covalently linked uteroglobin dimer (UGcl) by fusing two uteroglobin cDNAs via a synthetic linker sequence. Escherichia coli expressed UGcl bound progesterone with the same affinity as the native dimeric protein. Replacement of both tyrosines by phenylalanines abolished progesterone binding. Replacement of either the C-terminal tyrosine 21 or the N-terminal tyrosine 21' separately, reduced the affinity for progesterone 3- to 4-fold, suggesting that both tyrosines participate in progesterone binding. In contrast, substitutions of the threonine residues of the C- or N-terminal moities had no effect, whereas the replacement of both threonines reduced the affinity for progesterone 2- to 3-fold. These data, together with computer models, suggest that progesterone docks in the internal binding pocket of uteroglobin in two different orientations.

Amino Acid Sequence↗

PubMed1982

Interaction of oxidized and reduced uteroglobin with progesterone.

Binding of added progesterone to native uteroglobin requires the reduction of the disulfide bonds that hold together the two polypeptide chains of the protein. The hypothesis that in the native oxidized state of uteroglobin the steroid binding cavity is preformed and occupied by a progesterone molecule has been tested by several experimental means. The results demonstrate that progesterone does not interact with oxidized uteroglobin, and show that the majority of the oxidized uteroglobin molecules purified from pseudopregnant rabbits do not contain a progesterone molecule. Oxidation of reduced uteroglobin in the presence of saturating amounts of progesterone does not result in significant retention of the steroid inside the oxidized protein.

Amino Acid Sequence↗

PubMed1994

Two distinct factors bind to the rabbit uteroglobin TATA-box region and are required for efficient transcription.

The rabbit uteroglobin gene is expressed in a variety of epithelial cell types like the lung Clara cells and the glandular and luminal epithelial cells of the endometrium. Expression in Clara cells is on a high constitutive level, whereas expression in the rabbit endometrium is under tight hormonal control. One important element of the rabbit uteroglobin gene mediating its efficient transcription in two epithelial cell lines from human endometrium (Ishikawa) and lung (NCI-H441) is its noncanonical TATA box (TACA). Here, we show that two factors (TATA core factor [TCF] and TATA palindrome factor [TPF]) different from the TATA-box binding protein bind to the DNA major groove at two adjacent sites within the uteroglobin TATA-box region and that one of them (TCF) is specifically expressed in cell lines derived from uteroglobin-expressing tissues. The binding sites for TCF and TPF, respectively, are both required for efficient transcription in Ishikawa and NCI-H441 cells. Mutation of the TACA box, which we show is a poor TATA box in functional terms, to a canonical TATA motif does not affect TCF and TPF binding. Therefore, we suggest that the function of the unusual cytosine could be to reduce rabbit uteroglobin expression in cells lacking TCF and that the interaction of TATA-box binding protein with the weak TACA site is facilitated in TCF- and TPF-positive cells.

Animals↗

PubMed1996

Binding of YY1 to a site overlapping a weak TATA box is essential for transcription from the uteroglobin promoter in endometrial cells.

The gene for rabbit uteroglobin codes for a small calcium-, steroid-, and biphenyl metabolite-binding homodimeric protein which is expressed in a variety of epithelial cell types such as Clara cells (lung) and the glandular and luminal cells of the endometrium. One important region mediating its efficient transcription in a human endometrium-derived cell line, Ishikawa, is centered around a noncanonical TATA box. Two factors, TATA core factor (TCF), expressed in cell lines derived from uteroglobin-expressing tissues, and the ubiquitously expressed TATA palindrome factor, bind to the DNA major groove at two adjacent sites within this region. Here, we report the identification of the TATA palindrome factor as the transcription/initiation factor YY1 by microsequencing of the biochemically purified factor from HeLa cells. The binding site for YY1 within the uteroglobin gene is unique in its sequence and its location overlapping a weak TATA box (TACA). Binding of YY1 was required for efficient transcription in TCF-positive Ishikawa cells, which responded only weakly to a change of TACA to TATA, although in vitro binding affinity for the TATA-box-binding protein increased by 1 order of magnitude. In contrast, in CV-1 cells, lacking TCF, binding of YY1 was not required for transcription in the context of a wild-type TACA box, whereas a change from TACA to TATA led to significantly increased reporter gene expression. DNA binding data exclude a role of YY1 in stabilizing the interaction of the TATA-box-binding protein with the uteroglobin promoter. We conclude that cell lines derived from uteroglobin-expressing tissues overcome the weak TATA box with the help of auxiliary factors, one of them being YY1.

Adenoviridae↗

PubMed1978

Characteristics of the purified uteroglobin-like protein from rabbit lung.

A uteroglobin-like protein was prepared from lung extracts of female rabbits by absorption to immobilized anti-uteroglobin immunoglobulin and purified to homogeneity by gel filtration on Sephacryl S-200. The final preparation is indistinguishable from uteroglobin according to its behaviour in Ouchterlony double-diffusion, polyacrylamide gel electrophoresis under denaturing and non-denaturing conditions, ultraviolet spectrum, tryptic peptide analysis, and progesterone-binding properties. Progesterone binding to the lung protein exhibits an affinity similar to that observed with authentic uteroglobin and is equally enhanced by reduction of the protein with dithiothreitol. Competition experiments with non-radioactive steroids demonstrate a similar steroid-specificity for both proteins. Progesterone binding causes a perturbation in the ultraviolet absorbance of tyrosine residues of the lung protein similar to that observed with uteroglobin. These data suggest that the proteins prepared from both sources are biochemically identical.

Animals↗