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PubMed1991

Prolactin enhances uteroglobin gene expression by uteri of immature rabbits.

The effect of prolactin on uteroglobin production by immature rabbits was studied with neonatal (1 day old) and juvenile (14 days old) does. The animals were divided into 11 treatment groups for each age category and exposed to a 9-day injection protocol. Each day the animals received a subcutaneous injection of oestradiol-17 beta and/or ovine prolactin and/or progesterone, or were sham-injected. Juvenile animals, which received 100 micrograms oestradiol/kg 24 h-1, plus progesterone or plus prolactin and progesterone, produced detectable amounts of uteroglobin in the uterine secretions (0.034 +/- 0.010 mg uteroglobin/mg total protein and 0.098 +/- 0.03 l mg uteroglobin/mg total protein, respectively). None of the animals in the other juvenile treatment groups or any of the neonatal groups produced uteroglobin. From this survey it was apparent that uteroglobin secretion could be induced by exogenous oestradiol and progesterone in rabbits treated as early as 14 days of age, and that the added supplementation of prolactin enhanced the response to the ovarian steroids. As a result, additional juvenile animals were injected with 100 micrograms oestradiol +/- prolactin + progesterone and the effects of these two treatments were quantitated as follows: uteroglobin mRNA levels by slot-blot hybridization; endometrial surface area by computerized image analysis; and oestrogen, progesterone and prolactin receptors by immunocytochemistry. Prolactin modified the response of the juvenile rabbit uterus to oestradiol + progesterone for all parameters tested.

Animals↗
PubMed1992

Elements of the rabbit uteroglobin promoter mediating its transcription in epithelial cells from the endometrium and lung.

The rabbit uteroglobin gene is specifically expressed in certain epithelial cells of ontogenetically unrelated origin. In the endometrium, expression is restricted to the glandular and luminal epithelium and is inducible by progesterone and estradiol. In the lung, Clara cells lining the bronchiolar epithelium show constitutive expression of uteroglobin, which is modulated by glucocorticoids. To explore the molecular basis for this cell type specificity, we have transiently transfected the uteroglobin promoter region fused to the chloramphenicol acetyl transferase gene (CAT gene) in the endometrial cell line Ishikawa; in the human lung cell line NCI-H441, which shows morphological Clara cell characteristics; in HeLa cells; and in three fibroblast cell lines. The uteroglobin promoter efficiently drives expression of the CAT gene in Ishikawa and NCI-H441 cells, but not in HeLa and fibroblast cells. To identify the responsible elements we have analyzed progressive promoter 5'-deletion mutants and randomly generated linker scanning mutants spanning the sequence from -258 to -14 of the uteroglobin promoter. Transfection experiments reveal seven mutation-sensitive regions located around -30, -70, -95, -130, -190, -230, and -255. Several mutants display strong cell type-specific phenotypes. Most significantly, the integrity of the region around -190 is essential for full CAT gene expression in Ishikawa cells, but not in NCI-H441 cells.

Animals↗
PubMed1975

Binding of progesterone to the proteins of the uterine luminal fluid. Identification of uteroglobin as the binding protein.

1. The uterine luminal fluid of rabbits treated with estradiol and progesterone contains a protein factor with high affinity for [3-H] progesterone which is not present in the uterine secretion of control rabbits treated with estradiol. 2. This progesterone dependent factor is shown by gel filtration and polyacrylamide gel electrophoresis to be identical with the uterus specific protein uteroglobin, which seems to be required during the preimplantation phase. Uteroglobin specific antiserum, prepared in guinea pigs, completely inhibits the progesterone binding activity of the proteins of the uterine fluid. 3. Progesterone binding to uteroglobin is dependent upon millimolar concentrations of dithioerythritol. At saturation, one molecule of progesterone binds per uteroglobin molecule and the apparent association constant is 2 x 10-6 M-1 at 0 degrees C. 4. The progesterone binding species of uteroglobin exhibits a molecular weight of around 12 000 on polyacrylamide gels containing dodecylsulfate, and of 15 000 upon gel filtration, indicating a non-globular shape. This molecule is compased of two subunits of similar molecular size which are held together by a disulfide bridge among other forces.

Animals↗
PubMed1983

Immunocytochemical localization of uteroglobin in the genital tract of male rabbits.

Using the immunoperoxidase technique and specific goat anti-serum to uteroglobin, selective immunochemical staining products are localized in the epididymal epithelium of the caput and proximal corpus region, at the adluminal border of the cauda epididymidis and, as well known, in epithelial cells of the endometrium of pregnant and progesterone-treated rabbits. Specific staining is also seen on spermatozoa. A uteroglobin-like antigen has been similarly localized in alveolar and bronchial epithelial cells of the lung. Testis, prostate, seminal vesicle and ductus deferens do not seem to contain in their tissues immunoreactive uteroglobin-like antigens. Similarly, the uterus and ductus epididymidis of immature rabbits are devoid of immunoreactivity. The presence of uteroglobin-like antigens in tissues other than the endometrium, particularly the ductus epididymidis, stimulates new discussions on the function of this protein in reproductive physiology and fertility research.

Animals↗
PubMed1983

Specific interaction of some non-steroidal compounds with the progesterone binding site of uteroglobin.

Uteroglobin binds progesterone with high affinity. A few substituted diphenyl ketones were observed to inhibit uteroglobin-progesterone binding in a dose-dependent manner. 4,4'-Dimethoxy-2-hydroxy benzophenone had relatively higher affinity for uteroglobin. The structure-activity relationship amongst the substituted diphenyl ketones indicated considerable sensitivity towards minor structural modifications. These observations offer a tool to investigate nonsteroidal compounds in relation to progesterone related functions of uteroglobin in pregnancy.

Animals↗
PubMed1982

Uteroglobin-like antigens in species of Lagomorpha.

1. Uteroglobin-like antigens were found in the lung and uterus of the hare (Lepus) and the pika (Ochotona). These antigens presented an immunoreactivity indistinguishable from that of rabbit uteroglobin, as determined by radioimmunoassay. 2. The molecular weight and the subunit composition of these antigens were similar to those of rabbit uteroglobin as analyzed by SDS gel-electrophoresis. 3. Similar amounts of uteroglobin-like immunoreactivity were found in the respective lungs and uteri of hare and rabbit whereas the concentration of immunoreactivity in the pika organs was several-fold lower.

Animals↗
PubMed1991

Identification of residues essential for progesterone binding to uteroglobin by site-directed mutagenesis.

In order to identify amino acids directly involved in progesterone binding to rabbit uteroglobin we have mutated Phe 6, Tyr 21 and Thr 60 by site-directed mutagenesis of the uteroglobin cDNA. These residues have been postulated previously to participate in progesterone binding. High-level expression of the mutated uteroglobin cDNAs in Escherichia coli yields recombinant protein mutants that, like natural uteroglobin, form stable dimers, suggesting that the tertiary structure of the protein has not been altered. Substitution of Phe 6 by Ser or Ala does not change the progesterone binding characteristics. In contrast, replacement of Tyr 21 by Phe or Ala, drastically decreases progesterone binding. In addition, replacement of Thr 60 by Ala reduces the affinity for progesterone by a factor of three. These data suggest a direct interaction of progesterone with these two amino acids and support the idea of direct hydrogen bonding of the carbonyl (C3 and C20) of progesterone with the hydroxyl groups of Tyr 21 and Thr 60, respectively.

Animals↗
PubMed1986

Identification of a uteroglobin-like antigen in human uterine washings.

A uteroglobin-like molecule was detected with a sensitive radioimmunoassay for rabbit uteroglobin in the uterine washings of women. This antigen was detectable only in small amounts in the uterine washings obtained from women in the late luteal phase or proliferative phase, but was detected in large amounts in uterine washings of women collected during the early and midluteal phases of the ovarian-menstrual cycle. Our findings suggest that antigenically similar portions of rabbit uteroglobin have been phylogenetically conserved in women, and that endometrial production and secretion of this human uteroglobin-like antigen may be hormonally regulated.

Adult↗
PubMed1980

Interaction of S-carboxymethylated uteroglobin with progesterone.

S-Carboxymethylated uteroglobin, a small progesterone-binding globular protein, was studied by means of high-field proton magnetic resonance spectroscopy. Conformational changes induced by the steroid have been observed and indicate a well-defined rearrangement of the structure of the protein. The unusual stoichiometry of one progesterone to two uteroglobin dimers is confirmed by 1H NMR. His-8 plays a central role in the mechanism of interaction of uteroglobin with progesterone. The pH dependence of affinity constant for the complexation of the steroid parallels the titration of this histidine. Although it is not a part of the active site, it influences a crucial conformational transition of the protein through the charge carried by its imidazole ring. Formation of a tetramer of uteroglobin subunits able to bind progesterone is critically compared to a kinetic scheme involving only dimers.

Animals↗
PubMed1986

Nucleotide and derived amino acid sequences of a cDNA coding for pre-uteroglobin from the lung of the hare (Lepus capensis).

An almost full-length cDNA coding for pre-uteroglobin from hare lung was cloned and sequenced. The derived amino acid sequence indicated that hare pre-uteroglobin contained 91 amino acids, including a signal peptide of 21 residues. Comparison of the nucleotide sequence of hare pre-uteroglobin cDNA with that previously reported for the rabbit gene indicated five silent point substitutions and six others leading to amino acid changes in the coding region. The untranslated regions of both pre-uteroglobin mRNAs were very similar. The amino acid changes observed are discussed in relation to the different progesterone-binding abilities of both homologous proteins.

Amino Acid Sequence↗
PubMed1998

Solution structure of the recombinant oxidized rabbit uteroglobin using homonuclear and heteronuclear multidimensional NMR.

Rabbit uteroglobin (rab-UG) is a 16-kDa homodimeric secretory protein with potent anti-inflammatory/immunomodulatory properties. Its physiological role is still unclear, although it was observed that several small hydrophobic molecules bind to the oxidized and the reduced uteroglobin. It is suggested that the formation and/or disruption of the two disulphide bridges not only regulates this binding itself, but also the affinity to the ligand. The determination of the solution structure has been started with the assignment of 1H, 15N and 13C resonances of the oxidized rabbit uteroglobin, based on several two-dimensional and three-dimensional homonuclear and heteronuclear double and triple resonance experiments. The assignment was possible with the overproduction of the wild-type as well as of uniformly 15N-labeled and 15N/13C-labeled samples of the recombinant protein. A complete assignment of 1H, 15N and 13C resonances, the secondary-structure elements and the tertiary structure in solution is presented. The tertiary solution structure was found to be in good agreement with the previously determined crystal structure of rab-UG and with the solution structure of human uteroglobin (h-UG). h-UG and rab-UG are extremely stable proteins within a wide range of pH and temperatures. Some of the binding characteristics of ligands of rab-UG and a mutant with all cysteine residues exchanged to serine residues are discussed.

Amino Acid Sequence↗
PubMed1991

Novel upstream elements and the TATA-box region mediate preferential transcription from the uteroglobin promoter in endometrial cells.

To understand the mechanisms responsible for endometrium-specific expression of the uteroglobin gene, we have compared transcription from the uteroglobin promoter in a human endometrial cell line (Ishikawa) and in HeLa cells. In transient transfection experiments and in nuclear extracts, sequences from -395 to +14 of the uteroglobin gene are able to promote transcription of a reporter gene more efficiently in Ishikawa cells than in HeLa cells relative to the RSV or the SV40 early promoter. Analysis of progressive 5'-deletion mutants identifies three promoter regions, -258/-220, -205/-177, and -96/-35, that are important for preferential transcription in endometrial cells. DNase I footprinting experiments with nuclear extracts from Ishikawa and HeLa cells reveal a series of defined protections overlapping these regions. The relative intensity of individual protections differs between the two cell lines. Oligonucleotide competition experiments suggest that similar factor(s) bind(s) to the two relevant upstream regions of the promoter that share no homology to known regulatory elements. A protection over the TATA-box is detected only with extracts from Ishikawa cells. Band shift experiments show that an Ishikawa-specific factor binds to sequences overlapping the TATA-box region that are partially conserved in other endometrium-expressed genes. We propose that novel transcription factors mediate endometrium-specific expression of the uteroglobin gene in conjunction with a tissue-specific factor that binds to the TATA-box region.

Base Sequence↗
PubMed1992

Interchain cysteine bridges control entry of progesterone to the central cavity of the uteroglobin dimer.

The progesterone-binding protein uteroglobin has been expressed in Escherichia coli in an unfused, soluble form. Like mature uteroglobin from rabbit endometrium (UG), the E.coli produced uteroglobin (UG1) dimerizes in vitro, forms an antiparallel dimer with Cys3-Cys69' and Cys69-Cys3' disulfide bonds and binds progesterone under reducing conditions. In order to analyze the dimerization and the reduction dependence of progesterone binding in more detail, we separately replaced cysteine 3 and cysteine 69 by serines. Under reducing conditions, both uteroglobin variants (UG1-3Ser and UG1-69Ser) bind progesterone with the same affinity as the wild-type suggesting that both cysteine residues are not directly involved in progesterone binding. In contrast to the wild-type protein, both cysteine variants also bind progesterone with high affinity in the absence of reducing agents. In addition, UG1-3Ser and UG1-69Ser both form covalently linked homodimers. Thus, unnatural Cys69-69' and Cys3-3' disulfide bonds exist in UG1-3Ser and UG1-69Ser, respectively. These data together with computer models based on X-ray diffraction data strongly support the idea that progesterone reaches its binding site located in an internal hydrophobic cavity via a hydrophobic tunnel along helices 1 and 4. Under non-reducing conditions the tunnel is closed by two disulfide bridges (Cys3-Cys69' and Cys69-Cys3') that lie in the most flexible region of the dimer. Reduction or replacement of a cysteine residue enables conformational changes that open the channel allowing progesterone to enter.

Amino Acid Sequence↗
PubMed2000

Uteroglobin gene transcription: what's the RUSH?

Prolactin enhances progesterone-dependent transcription of the rabbit uteroglobin gene. RUSH transcription factors are implicated in the signal transduction pathway. The RUSH acronym identifies key features of these nuclear phosphoproteins, that is, RING-finger motif, binds the uteroglobin promoter, structurally related to the SWI/SNF family of transcription factors, and helicase-like. Cloned by recognition site screening, RUSH proteins bind to an 85-bp region (-170/-85) of the uteroglobin promoter that was subsequently identified as a novel prolactin-responsive region by promoter deletion analysis. Gel shift and linker-scanning assays further reduced the RUSH target site to -160/-110. A hexameric core of MCWTDK was identified as the RUSH-specific DNA-binding site (-126/-121) by CASTing. This site overlaps authentic HNF3 beta and OCT-1 binding sites. A unique Type IV P-type ATPase that is embedded in the inner nuclear membrane binds the RING domain of RUSH. The conformationally flexible loop portion of this RING-finger binding protein (RFBP) extends into the nucleoplasm to contact euchromatin. The physical association of RFBP with transcriptionally active chromatin supports the speculation that RFBP targets RUSH transcription factors to the active uteroglobin promoter.

Animals↗
PubMed1991

Expression of SV40 T antigen under control of rabbit uteroglobin promoter in transgenic mice.

The rabbit uteroglobin gene is expressed in the lungs and reproductive tracts of male and female rabbits. To examine whether the promoter region of the uteroglobin gene could be used to target a heterologous gene to the lungs of transgenic mice, a fusion gene consisting of 3.3 kb of the 5'-flanking region of the rabbit uteroglobin gene and the large T antigen gene of the SV40 virus was constructed and microinjected into the pronuclei of one-cell mouse embryos. Eleven founder transgenic mice (5 female and 6 male) were generated. Seven of these mice developed bronchioalveolar neoplasms. Four of the founder males also developed primitive undifferentiated urogenital tract tumors. One founder female and one female offspring of a founder male developed glandular paraovarian tumors. Northern analysis revealed that the predominant site of expression of the transgene was the lung. Immunohistochemical staining showed T antigen predominantly in epithelial cells lining the bronchioles, the submucosal glands of the trachea, and the neoplasms. There appeared to be a high level of mosaicism for the transgene in the founder mice, with poor transmission of the transgene to subsequent generations. This suggests that, under the control of the uteroglobin promoter, the T antigen gene may be lethal to the fetus.

Animals↗
PubMed1992

Purified uteroglobin lacks anti-proteinase activity.

Rabbit uteroglobin was purified from both uterine fluids and lung lavages by a combination of gel filtration and ion-exchange column chromatography. Anti-trypsin and anti-papain activities were measured in the fractions of the eluates. Anti-proteinase activities were detected in minor contaminants eluting close to the uteroglobin peak but the protein itself was devoid of anti-proteinase activity. Ion-exchange-purified uteroglobin also lacked inhibitory activity of elastase, chymotrypsin or subtilisin. The presence of contaminants could explain the anti-proteinase activity reported occasionally for uteroglobin.

Amino Acid Sequence↗
PubMed1976

Uteroglobin and related biochemical changes in the reproductive tract during early pregnancy in the rabbit.

The macromolecular secretion products of the rabbit uterus are described. The biochemical and biological properties of uteroglobin are considered, and its synthesis and secretion in various endocrinological conditions are described. The release of uteroglobin from the endometrial epithelium is stimulated by progestagens such as progesterone and its synthetic analogues, although its synthesis has not yet been shown to be entirely dependent on progesterone. The biological function of uteroglobin is obscure. Several approaches to this long-standing probelm are discussed, including the passage of uteroglobin into the blastocyst. It is suggested that interference with the passage of uterine components into the blastocyst may inhibit implantation and provide a means of contraception.

Animals↗
PubMed1993

Human Clara cell 10-kDa protein is the counterpart of rabbit uteroglobin.

Human Clara cell 10-kDa protein has been suggested to be a counterpart of rabbit uteroglobin, an immunomodulatory and antiinflammatory secretory protein. Since this human protein is not readily available in substantial quantity for detailed characterization of its biochemical, biological, and pharmacological properties, we sought to express it in Escherichia coli in order to study its structure-function relationship. However, bacterial overproduction of homodimeric proteins with interchain disulfide bonds, such as Clara cell 10-kDa protein, was thought to be impossible until we achieved expression of native uteroglobin (Miele, L., Cordella-Miele, E., and Mukherjee, A.B. (1990) J. Biol. Chem. 265, 6427-6435). Here, we report high level production of recombinant native dimeric human Clara cell 10-kDa protein in E. coli and its characterization. Recombinant human Clara cell 10-kDa protein forms its disulfide bonds within the bacterial cytoplasm. The purified protein possesses two of the most important activities characteristic of uteroglobin: (i) it is an excellent substrate of transglutaminase, and (ii) it is a potent inhibitor of porcine pancreatic and, more importantly, human synovial phospholipase A2. These results demonstrate that human Clara cell 10-kDa protein and rabbit uteroglobin have very similar biochemical properties. Our data suggest that this protein may possess immunomodulatory and antiinflammatory activities of potential physiological and pharmacological importance.

Amino Acid Sequence↗