Glycobiology Advance Access originally published online on November 30, 2005
Glycobiology 2006 16(3):39R-45R; doi:10.1093/glycob/cwj059
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REVIEW |
Meet the multifunctional and sexy glycoforms of glycodelin
2 Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel; and 3 Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
1 To whom correspondence should be addressed; e-mail: nathan.sharon{at}weizmann.ac.il
Accepted on November 8, 2005
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Abstract |
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 Top Abstract IntroductionGlycodelin structureIn contraceptionIn immunosuppressionEpilogueAcknowledgmentsReferences |
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Glycodelin, a human-secreted glycoprotein that appears in a small number of glycoforms, exhibits diverse biological activities, such as in contraception and immunosuppression. Moreover, different tissue-specific glycoforms appear to mediate diverse functions. Quite unusually, the glycodelin N-linked glycans differ between the male and female glycoforms. The fact that these glycans are fundamental for exerting the physiological activities of the different glycoforms, makes them an interesting target for glycobiology research. This review will focus on the involvement of the glycans in glycodelin activity and compare between the several glycoforms.
Key words: contraception / glycans / immunosuppression / oocyte / sperm
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Introduction |
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TopAbstractIntroductionGlycodelin structureIn contraceptionIn immunosuppressionEpilogueAcknowledgmentsReferences |
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Since the late 1970s, several investigators have independently identified a glycoprotein from human placenta, amniotic fluid, pregnancy decidua, and seminal plasma and thus different names were given, such as glycodelin (the conventional name) (Dell et al., 1995
), Placental Protein 14 (PP14, even though it is not of placental origin) (Bohn et al., 1982), and progesterone-associated endometrial protein (PAEP) (Joshi et al., 1980). Glycodelin is a glycoprotein that belongs to the lipocalin superfamily, of which most members are extracellular proteins that function in transporting small hydrophobic ligands (Kontopidis et al., 2004). The primary sequence of glycodelin shows high homology with that of ß-lactoglobulin (ßLG), a milk protein that is not expressed in humans (Julkunen et al., 1988) (Figure 1a). Nevertheless, these two do not have similar functions. Glycodelin appears in various glycoforms (reviewed in Seppala et al., 2002) (Table I): The glycodelin amniotic glycoform (designated as the GdA glycoform) is found in the uterus, where it is the major progesterone-regulated glycoprotein secreted into the uterine luminal cavity by secretory/decidualized endometrial glands. Other tissues expressing glycodelins (Table II) include follicular fluid (designated as the GdF glycoform) and seminal vesicle (designated as the GdS glycoform). Quite remarkably, GdA and GdF potently and dose-dependently inhibit human sperm–oocyte binding, whereas GdS, that is differently glycosylated, has no such effect (Morris et al., 1996; Chiu et al., 2003b). GdA is essentially undetectable in proliferative phase endometrium and is dramatically up-regulated during the secretory phase of the ovulatory cycle and in early pregnancy (Julkunen M., Koistinen R., et al., 1986; Julkunen M., Wahlstrom T., et al., 1986). Its absence in the uterus during the periovulatory midcycle is consistent with the open "fertile window." GdA induced by local or systemic administration of progestogens may reduce the fertilizing capacity of sperm in any phase of the menstrual cycle. The immunosuppressive activity of GdA, which depends on the nature of its N-linked glycans, may contribute to protection of the embryonic semiallograft at the feto–maternal interface (Bolton et al., 1987). GdS does not manifest any of these effects but has been shown recently to maintain the uncapacitated state of human sperm (Chiu et al., 2005).
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In this review, we shall discuss primarily the properties of the glycodelins that are affected by the nature of their glycans. Other functions of glycodelin, such as being an epithelial differentiation marker, or its role in glandular morphogenesis (Seppala et al., 2002), will not be dealt with, because they are glycosylation independent. Neither shall we dwell on endocrinological, genetical, clinical, and other aspects of glycodelin, which are not directly related to its glycobiolgical properties, and which have been reviewed in detail elsewhere (Seppala et al., 2002).
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Glycodelin structure |
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TopAbstractIntroductionGlycodelin structureIn contraceptionIn immunosuppressionEpilogueAcknowledgmentsReferences |
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Glycodelin, that is usually purified from the decidua or the amniotic fluid, has an apparent molecular weight of 28 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS–PAGE), whereas in gel filtration, it behaves as a homodimeric form of
60 kDa (Vigne et al., 2001). The primary structure of the mature protein consists of 162 amino acids, wherein four cysteine residues form intermolecular disulfide bridges (Julkunen et al., 1988). These are conserved, because they are also observed in the homologous ßLG. The tertiary structure of glycodelin was deduced using bovine ßLG crystal-derived structure as a template, and the two structures were found to be very similar (Figure 1a). High similarity was manifested by the circular dichroism spectra of the two proteins a well (Koistinen et al., 1999). Both ßLG and GdA contain significant amount of ß sheets and expose two nonpolar surface regions. This had led Koistinen et al. (1999) to examine their functional similarity by thin-layer chromatography and fluorescence quenching methods. It was found that unlike bovine ßLG, glycodelin was not able to bind either retinoids nor any endogenous hydrophobic ligands. Protein stability measurement by differential scanning calorimetry, at physiological pH, showed a significant difference between the two proteins.
Of the three potential N-linked glycosylation sites of glycodelin, namely Asn28, Asn63, and Asn85, only the first two are glycosylated. Notably, in ßLG there are no consensus N-linked glycosylation sites (Julkunen et al., 1988). According to the tertiary structure model of glycodelin, these glycans are located in a way which would allow them to form a clustered saccharide patch on the protein surface (Koistinen et al., 1999). Dell et al. (1995) and Morris et al. (1996) used strategies based upon fast atom bombardment and electrospray mass spectroscopy to obtain information on the glycosylation patterns of GdA and GdS (reviewed in Dell and Morris, 2001). GdA, that contains 17.5% carbohydrate by weight, was shown to carry at Asn28 oligomannose, hybrid and complex-type structures, whereas at Asn63 only complex-type glycans were found (Figure 1b). The major biantennary oligosaccharides present at both sites consist of sialylated or fucosylated GalNAcß(1–4)GlcNAc(LacdiNAc) sequences, which are rare in higher animals, although they are present in pituitary glycoprotein hormones, where they are sulfated and play a role in regulating their circulatory half-life (reviewed in Woodworth and Baenziger, 2001). It was suggested that there could be a coordinated expression of ß4-GalNAc-transferase and 
(2–6)-sialyltransferase in cells that synthesize sialylated LacdiNAc structures (Dell et al., 1995). This question was confirmed in an experiment, in which recombinant GdA was produced in two different cell lines (Van den Nieuwenhof et al., 2000): wild-type CHO cells that lack the ß4-GalNAc-transferase and HEK293 cells that express it. Indeed, the GdA product in CHO cells was devoid of any LacdiNAc-containing glycans and carried only Galß(1–4)GlcNAc (LacNAc)-type glycans, whereas in HEK293 cells, the same glycans were present as in native GdA.
Purified glycodelins from secretory-phase endometrium, first-trimester decidua, and midtrimester amniotic fluid were similar regarding isoelectric points, reactions with Wisteria floribunda or Sambucus nigra lectins (that recognize GalNAc and NeuAc(2–6)GalNAc, respectively) and sperm–oocyte binding inhibition, therefore legitimizing the use of the term GdA for all (Koistinen et al., 2003).
Analysis of the N-glycans of GdS, the seminal plasma glycoform, revealed that unlike GdA, GdS contains no sialylated glycans and is unusually rich in fucose (Morris et al., 1996). Its major complex-type biantennary oligosaccharides, at Asn63, are composed of Galß(1–4)[Fuc(1–3)]GlcNAc (Lewisx) and Fuc(1–2)Galß(1–4)[(Fuc(1–3)]GlcNAc (Lewisy) sequences. Lewisy is a relatively rare oligosaccharide in humans and is generally considered as a tumor and apoptosis-associated antigen (Hiraishi et al., 1993). At Asn28 of GdS, only oligomannose structures were found. The difference in glycosylation was confirmed by lectin-binding studies showing that, unlike GdA, GdS does not react with W. floribunda or S. nigra lectins (Koistinen et al., 1996). GdA and GdS have identical primary structures, immunoreactivity, tryptic peptide profiles, and similar thermodynamic parameters of reversible denaturation (Koistinen et al., 1996, 1999), implying that the differences in their glycosylation patterns do not affect their way of folding. No such comparison was done with the GdF glycoform.
GdF, a novel glycoform, formerly known as ZIF-1 (Zona binding Inhibitory Factor-1) (Chiu et al., 2003a), is secreted to the follicular fluid and shares similar properties with GdA. However, it is differently glycosylated, as demonstrated by fluorophore-assisted carbohydrate electrophoresis, lectin-binding assays and isoelectric focusing (Chiu et al., 2003b). For instance, GdF binding to succinylated wheat germ agglutinin was stronger than that of GdA, indicating of higher GlcNAc content in the former glycoform.
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In contraception |
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TopAbstractIntroductionGlycodelin structureIn contraceptionIn immunosuppressionEpilogueAcknowledgmentsReferences |
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Prevention of unnecessary fertilization is required during early gestation and most of the menstrual cycle. GdA was the first endogenous glycoprotein found to potently and dose-dependently inhibit binding of human sperm to the oocyte zona pellucida (ZP) (Oehninger et al., 1995
). These studies employed the "Hemizona Assay" (Yao et al., 1996), where the human oocyte is microbisected to generate two hemispheres, so as to prevent fertilization. The binding of fertile sperm to the two hemispheres is examined in the presence and absence of a test substance.
Whereas GdA efficiently inhibited the binding of the sperm to the oocyte, GdS was unable to do so, supporting the notion that GdA mediates this biological activity via its unusual oligosaccharide sequences, which are not present in GdS from seminal plasma (Morris et al., 1996). This effect appears to result from interaction between glycodelin and the sperm rather than between glycodelin and the oocyte (Figure 2). Indirect immunofluorescence staining revealed specific binding of GdA and GdF to the acrosome region of human spermatozoa (Chiu et al., 2003b). This interaction between the spermatozoa and GdA, as well as GdF, does not affect the motility, viability, and acrosomal status of the treated spermatozoa (Chiu et al., 2003a).
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A binding kinetics study using 125I-labeled GdF demonstrated two binding sites on human spermatozoa, a low-affinity site and a high-affinity one (Chiu et al., 2003a). For GdA, a single binding site on the spermatozoa was found, with an affinity close to that of the low-affinity site of GdF. Further studies demonstrated that ZP-isolated fractions reduced the binding of radio-labeled GdF and GdA to sperm extract (Chiu et al., 2004). It was also demonstrated that the glycodelin-binding sites were on the outer acrosomal membrane or in the sperm plasma membrane overlaying the acrosome, although the relevant receptors have not been identified.
The interactions of the individual glycodelins with sperm are carbohydrate specific, whereas the binding of GdA was inhibited by mannose and fucose that of GdF was inhibited by GlcNAc in addition to fucose and mannose (Chiu et al., 2004). Mannose- and fucose-containing neoglycoproteins suppressed the binding of GdA to sperm to a greater extent than that of GdF (Chiu et al., 2003a). One possible explanation is that GdF has an additional high-affinity binding site on sperm that GdA lacks. The involvement of mannose, fucose, and GlcNAc residues in binding is supported by the finding that pretreatment of the glycodelins with -mannosidase, -fucosidase, or ß-N-acetylglucosaminidase (in this case GdF only) abolishes the binding to sperm (Chiu et al., 2004). The enzyme ß4-galactosyltransferase (GalT) has been proposed to be involved in sperm–oocyte interaction by binding GlcNAc residues on the oocyte glycoprotein ZP3 (reviewed in Nixon et al., 2001) but has been ruled out as a possible receptor for glycodelin. GalT inhibitors, such as UDP-Gal or -lactalbumin and GalT-activity modifiers did not abrogate GdA- and GdF-specific binding (Chiu et al., 2004). Thus, the nature of the glycodelin receptor(s) on sperm is still a mystery.
GdS is one of the most abundant glycoproteins in seminal plasma (Koistinen et al., 2000) and unlike GdA or GdF, it does not inhibit sperm–ZP binding (Chiu et al., 2003a). Recently, two low-affinity binding sites for GdS were found on the sperm head, which are different form the acrosomal GdA-/GdF-binding sites (Chiu et al., 2005). In addition, GdS has been shown to be one of the factors responsible for maintaining the uncapacitated state of human sperm in seminal plasma.
Intriguingly, GdF, that is synthesized in luteinized granulosa cells (the ovarian follicle wall), can be taken up by cumulus cells (nutrient cells that surround the oocyte) and to undergo partial de-glycosylation (Tse et al., 2002). To account for this finding, Chiu et al. (2005) have suggested an appealing sequence of events: At first, seminal plasma-derived GdS is removed from spermatozoa as they migrate across the cervical mucus, initiating capacitation. Subsequently, follicular fluid-derived GdF in the oviduct attaches on the acrosome region of sperm head to prevent the premature acrosome reaction. GdF is then removed by the cumulus cells and undergoes partial de-glycosylation to turn it inactive. As a result, sperm–oocyte binding capacity is restored and progesterone-induced acrosome reaction is induced to initiate the fertilization process.
Because GdA is able to inhibit sperm–ZP interaction and GdS is not, it was interesting to examine whether abnormal glycosylation of seminal plasma glycodelin occurs in infertile males (Koistinen et al., 2000). GdS with GdA-like oligosaccharides could be related to reduced fertilization capacity of sperm. Even though such variations were found to occur in GdS, analysis of GdS level in seminal plasma had little value in the prediction of fertilizing potential of sperm.
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In immunosuppression |
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TopAbstractIntroductionGlycodelin structureIn contraceptionIn immunosuppressionEpilogueAcknowledgmentsReferences |
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Implantation involves an intimate contact between two genetically disparate organisms, the embryo (trophoblast) and the mother (decidua). Despite being a semiallograft, the human fetus survives maternal rejection during normal pregnancy. Glycodelin is believed to act by suppressing immune reactions at the feto–maternal interface. Amniotic fluid or purified GdA inhibited T-cell activation and proliferation by phytohemagglutinin (PHA) or other agents (but not by concanavalin A), as evidenced by a decrease of 3H-thymidine uptake or interleukin-2 (IL-2) production (Pockley et al., 1988
, 1989; Rachmilewitz et al., 1999). The amniotic fluid inhibitory activity was abrogated after depletion of GdA by an immunoaffinity column (Bolton et al., 1987). The inhibition was mediated by an apoptotic effect on activated T cells (Mukhopadhyay et al., 2001). GdS was not apoptotically active, raising the question whether the GdA-specific oligosaccharides are involved in the apoptotic activity. This apoptotic activity was indeed found to require the presence of sialic acid on the complex glycans (which are sialylated in GdA). Expression of glycodelin in yeasts, that lack sialic acid, as well as enzymatic desialylation of GdA, resulted in inactive forms of glycodelin (Mukhopadhyay et al., 2004). GdS which lacks sialic acid was inactive as well. Nevertheless, a subsequent study demonstrated that a mutant form of glycodelin, in which the Asn28 and Asn63 residues were mutated into Gln to abolish glycosylation, still retained its anti-proliferative activity (Jayachandran et al., 2004). It was therefore concluded that the immunosuppressive activity actually resides in the glycodelin protein backbone, while the oligosaccharides play either permissive or nonpermissive roles in the manifestation of this activity. The sialylated glycans on GdA might expose its apoptosis-inducing activity, whereas high fucosylation and lack of sialylation on GdS would keep it inactive. GdA was shown to bind to CD45 among other unidentified receptors on T cells (Rachmilewitz et al., 2003). The researchers suggested that it might behave as a lectin, like galectin-1 which is able to recognize carbohydrates on CD45 and induces, as a result, apoptosis in T cells.
Most of the lymphocytes that lodge in the uterus are large granular lymphocyte (LGL) natural killer (NK) cells (reviewed in Moffett-King, 2002). The K562 erythroleukemia cell line is a standard experimental target for NK cells-mediated lysis, which becomes, however, resistant to NK killing upon induced differentiation (Dokhelar et al., 1984). Purified GdA is able to inhibit LGL NK cell-mediated lysis (Okamoto et al., 1991). Surprisingly, glycodelin was found to be secreted as such from the differentiated K562 cells, explaining their resistance to the lysis (Morrow et al., 1992). A unique subset of decidual NK cells, which usually exhibit an immunomodulatory potential, were themselves found to express glycodelin, proposing a role for these cells in the feto–maternal defense system (Koopman et al., 2003).
GdA has been also shown to partially regulate B-cell activation (e.g., diminishing IgM secretion and Major Histocompatibility Complex class II expression) as well as B-cell proliferation, in a glycosylation-dependent manner (Yaniv et al., 2003). CD22, a siglec that is a negative regulator of B-cell activation, binds to 2,6- linked sialic acid residues on glycoproteins (Powell et al., 1993). Because GdA is sialylated, one of the suggested mechanisms of suppressing B cells is via specific CD22–GdA interaction, but this is yet to be determined.
GdA inhibits monocytes chemoattractant induced migration but is not capable of triggering apoptosis in monocytes (Mukhopadhyay et al., 2001). It has been shown to bind to a specific receptor on CD14+ monocytes/macrophages (Miller et al., 1998). However, this interaction was glycosylation independent.
It seems that GdA does not act alone, and two other "carrier" glycoproteins have been demonstrated to combine with as well as to potentiate GdA’s immunosuppressive activity; these are the serum 2-macroglobulin (Riely et al., 2000) and the more potent uterine pregnancy zone protein (Skornicka et al., 2004).
Although bone marrow is not present at the feto–maternal interface, it is an integral part of the hematopoietic system, and glycodelin was shown to be expressed in this tissue. Among other hematopoietic cells, glycodelin is expressed in erythroid precursors but not in mature erythrocytes (Kamarainen et al., 1994). Moreover, it is present along the megakaryocytic lineage as well as in mature platelets (Morrow et al., 1994). Interestingly, genes for human glycodelin and for the ABO blood group antigens are mapped on same chromosomal band, 9q34 (Van Cong et al., 1991). Still, although the latter are abundant in mature erythrocytes glycodelin is not. Two spliced variants of hematopoietic glycodelin are expressed at the RNA level (Morrow et al., 1994), one of which is shorter, but no function has been assigned to it yet. The peculiar expression of hematopoietic glycodelin and its role in the bone marrow remain to be elucidated.
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Epilogue |
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TopAbstractIntroductionGlycodelin structureIn contraceptionIn immunosuppressionEpilogueAcknowledgmentsReferences |
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The glycodelin glycoforms seem to be one of the rare cases, in which the same protein is glycosylated differently in males and females, which raises the intriguing question of how this occurs. The glycodelin glycoforms also serve as an impressive model to illustrate the importance of protein glycosylation for biological activity. The glycodelin glycosylation variety seems to be expanding and getting more complex, as more glycoforms are discovered, especially in the unexplored regions outside of the reproductive system, such as the bone marrow. Although information on the oligosaccharides of glycodelin that disrupt the sperm–oocyte interaction has been presented, their receptors on the sperm have not been identified. The mechanisms that underlie the immunosuppressive role of glycodelin are poorly understood. Nevertheless, considerable amount of data is beginning to accumulate on the glycodelin-binding sites on leukocytes, on its triggered signal transduction, on changes in cytokines profile, and so on. One mechanism suggested is that GdA elevates T-cells activation threshold in a so-called "rheostatic" manner (Rachmilewitz et al., 2001
). The expression of the hematopoietic glycodelin by the megakaryocytic lineage has been suggested to indicate a regulatory link between blood coagulation and the immune systems (reviewed in Tykocinski et al., 1996) but has not been examined. Here, we suggest that its presence in the bone marrow may indicate an immunosuppressive activity or rather an "immunoprotective" activity on differentiating blasts of the erythroid and megakaryocytic lineages. Immunosuppressive activity by nucleated-erythroid cells has been observed before (reviewed in Kozlov, 2002). This so-called "protective effect" can be tested in a glycodelin knockout murine model. Lack of glycodelin in the hematopoietic system would be quite restrictive, in contrary to that in the reproductive system, and perhaps will have a direct effect. There is a continuing observation that the same unusual carbohydrate structures associated with the immunosuppressive effect of glycodelin are also expressed on intravascular helminthic parasites, on Helicobacter pylori, on tumor cells, and on HIV-infected T lymphocytes (reviewed in Clark et al., 1997). It is therefore possible that these structures might assist the pathogens and infected/transformed cells to escape efficient host immune reactions. In conclusion, glycodelin is a remarkable example of the increasing importance of the glycobiological aspect for the understanding of how co- and posttranslational events affect the biological activity of proteins in health and disease. |
Acknowledgments |
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TopAbstractIntroductionGlycodelin structureIn contraceptionIn immunosuppressionEpilogueAcknowledgmentsReferences |
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This review is based on a term paper submitted by K.L. in fulfillment of the requirement of a course on the Molecular Biology of Glycoproteins and Glycolipids, given by N.S. in the winter semester 2004/2005 at the Feinberg Graduate School of the Weizmann Institute of Science.
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Abbreviations |
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GdA, glycodelin A (amniotic); GdF, glycodelin F (follicular); GdS, glycodelin S (seminal); LacdiNAc, GalNAcß (1–4)GlcNAc; LGL, large granular lymphocytes; NK, natural killer; ZP, zona pellucida; ßLG, ß-lactoglobulin
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References |
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TopAbstractIntroductionGlycodelin structureIn contraceptionIn immunosuppressionEpilogueAcknowledgmentsReferences |
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Bohn, H., Kraus, W., and Winckler, W. (1982) New soluble placental tissue proteins: their isolation, characterization, localization and quantification. Placenta Suppl., 4, 67–81.[Medline]
Bolton, A.E., Pockley, A.G., Clough, K.J., Mowles, E.A., Stoker, R.J., Westwood, O.M., and Chapman, M.G. (1987) Identification of placental protein 14 as an immunosuppressive factor in human reproduction. Lancet, 1, 593–595.[ISI][Medline]
Chiu, P.C., Chung, M.K., Tsang, H.Y., Koistinen, R., Koistinen, H., Seppala, M., Lee, K.F., and Yeung, W.S. (2005) Glycodelin-S in human seminal plasma reduces cholesterol efflux and inhibits capacitation of spermatozoa. J. Biol. Chem., 280, 25580–25589.
Chiu, P.C., Koistinen, R., Koistinen, H., Seppala, M., Lee, K.F., and Yeung, W.S. (2003a) Binding of zona binding inhibitory factor-1 (ZIF-1) from human follicular fluid on spermatozoa. J. Biol. Chem., 278, 13570–13577.
Chiu, P.C., Koistinen, R., Koistinen, H., Seppala, M., Lee, K.F., and Yeung, W.S. (2003b) Zona-binding inhibitory factor-1 from human follicular fluid is an isoform of glycodelin. Biol. Reprod., 69, 365–372.
Chiu, P.C., Tsang, H.Y., Koistinen, R., Koistinen, H., Seppala, M., Lee, K.F., and Yeung, W.S. (2004) The contribution of D-mannose, L-fucose, N-acetylglucosamine, and selectin residues on the binding of glycodelin isoforms to human spermatozoa. Biol. Reprod., 70, 1710–1719.
Clark, G.F., Dell, A., Morris, H.R., Patankar, M., Oehninger, S., and Seppala, M. (1997) Viewing AIDS from a glycobiological perspective: potential linkages to the human fetoembryonic defence system hypothesis. Mol. Hum. Reprod., 3, 5–13.
Dell, A. and Morris, H.R. (2001) Glycoprotein structure determination by mass spectrometry. Science, 291, 2351–2356.
Dell, A., Morris, H.R., Easton, R.L., Panico, M., Patankar, M., Oehniger, S., Koistinen, R., Koistinen, H., Seppala, M., and Clark, G.F. (1995) Structural analysis of the oligosaccharides derived from glycodelin, a human glycoprotein with potent immunosuppressive and contraceptive activities. J. Biol. Chem., 270, 24116–24126.
Dokhelar, M.C., Garson, D., Wakasugi, H., Tabilio, A., Testa, U., Vainchenker, W., and Tursz, T. (1984) K562 cells induced to differentiate by phorbol ester tumor promotors resist NK lysis. Cell Immunol., 87, 389–399.[CrossRef][ISI][Medline]
Hiraishi, K., Suzuki, K., Hakomori, S., and Adachi, M. (1993) Le(y) antigen expression is correlated with apoptosis (programmed cell death). Glycobiology, 3, 381–390.
Horowitz, I.R., Cho, C., Song, M., Flowers, L.C., Santanam, N., Parthasarathy, S., and Ramachandran, S. (2001) Increased glycodelin levels in gynecological malignancies. Int. J. Gynecol. Cancer, 11, 173–179.[CrossRef][ISI][Medline]
Jayachandran, R., Shaila, M.S., and Karande, A.A. (2004) Analysis of the role of oligosaccharides in the apoptotic activity of glycodelin A. J. Biol. Chem., 279, 8585–8591.
Joshi, S.G., Smith, R.A., and Stokes, D.K. (1980) A progestagen-dependent endometrial protein in human amniotic fluid. J. Reprod. Fertil., 60, 317–321.[Abstract]
Julkunen, M. (1986) Human decidua synthesizes placental protein 14 (PP14) in vitro. Acta Endocrinol. (Copenh)., 112, 271–277.[Medline]
Julkunen, M., Koistinen, R., Sjoberg, J., Rutanen, E.M., Wahlstrom, T., and Seppala, M. (1986) Secretory endometrium synthesizes placental protein 14. Endocrinology, 118, 1782–1786.[Abstract]
Julkunen, M., Rutanen, E.M., Koskimies, A., Ranta, T., Bohn, H., and Seppala, M. (1985) Distribution of placental protein 14 in tissues and body fluids during pregnancy. Br. J. Obstet. Gynaecol., 92, 1145–1151.[ISI][Medline]
Julkunen, M., Seppala, M., and Janne, O.A. (1988) Complete amino acid sequence of human placental protein 14: a progesterone-regulated uterine protein homologous to beta-lactoglobulins. Proc. Natl. Acad. Sci. U. S. A., 85, 8845–8849.
Julkunen, M., Wahlstrom, T., and Seppala, M. (1986) Human fallopian tube contains placental protein 14. Am. J. Obstet. Gynecol., 154, 1076–1079.[ISI][Medline]
Julkunen, M., Wahlstrom, T., Seppala, M., Koistinen, R., Koskimies, A., Stenman, U.H., and Bohn, H. (1984) Detection and localization of placental protein 14-like protein in human seminal plasma and in the male genital tract. Arch. Androl., 12 (Suppl.), 59–67.
Kamarainen, M., Halttunen, M., Koistinen, R., von Boguslawsky, K., von Smitten, K., Andersson, L.C., and Seppala, M. (1999) Expression of glycodelin in human breast and breast cancer. Int. J. Cancer, 83, 738–742.[CrossRef][ISI][Medline]
Kamarainen, M., Leivo, I., Koistinen, R., Julkunen, M., Karvonen, U., Rutanen, E.M., and Seppala, M. (1996) Normal human ovary and ovarian tumors express glycodelin, a glycoprotein with immunosuppressive and contraceptive properties. Am. J. Pathol., 148, 1435–1443.[Abstract]
Kamarainen, M., Miettinen, M., Seppala, M., von Boguslawsky, K., Benassi, M.S., Bohling, T., and Andersson, L.C. (1998) Epithelial expression of glycodelin in biphasic synovial sarcomas. Int. J. Cancer, 76, 487–490.[CrossRef][ISI][Medline]
Kamarainen, M., Riittinen, L., Seppala, M., Palotie, A., and Andersson, L.C. (1994) Progesterone-associated endometrial protein – a constitutive marker of human erythroid precursors. Blood, 84, 467–473.
Kamarainen, M., Seppala, M., Virtanen, I., and Andersson, L.C. (1997) Expression of glycodelin in MCF-7 breast cancer cells induces differentiation into organized acinar epithelium. Lab. Invest., 77, 565–573.[ISI][Medline]
Koistinen, H., Easton, R.L., Chiu, P.C., Chalabi, S., Halttunen, M., Dell, A., Morris, H.R., Yeung, W.S., Seppala, M., and Koistinen, R. (2003) Differences in glycosylation and sperm-egg binding inhibition of pregnancy-related glycodelin. Biol. Reprod., 69, 1545–1551.
Koistinen, H., Koistinen, R., Dell, A., Morris, H.R., Easton, R.L., Patankar, M.S., Oehninger, S., Clark, G.F., and Seppala, M. (1996) Glycodelin from seminal plasma is a differentially glycosylated form of contraceptive glycodelin-A. Mol. Hum. Reprod., 2, 759–765.
Koistinen, H., Koistinen, R., Hyden-Granskog, C., Magnus, O., and Seppala, M. (2000) Seminal plasma glycodelin and fertilization in vitro. J. Androl., 21, 636–640.[Abstract]
Koistinen, H., Koistinen, R., Seppala, M., Burova, T.V., Choiset, Y., and Haertle, T. (1999) Glycodelin and beta-lactoglobulin, lipocalins with a high structural similarity, differ in ligand binding properties. FEBS Lett., 450, 158–162.[CrossRef][ISI][Medline]
Kontopidis, G., Holt, C., and Sawyer, L. (2004) Invited review: beta-lactoglobulin: binding properties, structure, and function. J. Dairy Sci., 87, 785–796.
Koopman, L.A., Kopcow, H.D., Rybalov, B., Boyson, J.E., Orange, J.S., Schatz, F., Masch, R., Lockwood, C.J., Schachter, A.D., Park, P.J., and Strominger, J.L. (2003) Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J. Exp. Med., 198, 1201–1212.
Kozlov, V.A. (2002) Molecular mechanisms of the immunosuppressive effect of erythroid cells. Russ. J. Immunol., 7, 211–218.[Medline]
Miller, R.E., Fayen, J.D., Chakraborty, S., Weber, M.C., and Tykocinski, M.L. (1998) A receptor for the lipocalin placental protein 14 on human monocytes. FEBS Lett., 436, 455–460.[CrossRef][ISI][Medline]
Moffett-King, A. (2002) Natural killer cells and pregnancy. Nat. Rev. Immunol., 2, 656–663.[CrossRef][ISI][Medline]
Morris, H.R., Dell, A., Easton, R.L., Panico, M., Koistinen, H., Koistinen, R., Oehninger, S., Patankar, M.S., Seppala, M., and Clark, G.F. (1996) Gender-specific glycosylation of human glycodelin affects its contraceptive activity. J. Biol. Chem., 271, 32159–32167.
Morrow, D.M., Getty, R.R., Riittinen, L., Seppala, M., and Tykocinski, M.L. (1992) Expression of the immunosuppressive molecule placental protein 14 (PP14) by the myelogenous leukemic cell line K562. In Keystone Symposium on Molecular and Cellular Biology. Tamarran, Denver, CO, pp. 00–00.
Morrow, D.M., Xiong, N., Getty, R.R., Ratajczak, M.Z., Morgan, D., Seppala, M., Riittinen, L., Gewirtz, A.M., and Tykocinski, M.L. (1994) Hematopoietic placental protein 14. An immunosuppressive factor in cells of the megakaryocytic lineage. Am. J. Pathol., 145, 1485–1495.[Abstract]
Mukhopadhyay, D., Sundereshan, S., Rao, C., and Karande, A.A. (2001) Placental protein 14 induces apoptosis in T cells but not in monocytes. J. Biol. Chem., 276, 28268–28273.
Mukhopadhyay, D., SundarRaj, S., Alok, A., and Karande, A.A. (2004) Glycodelin A, not glycodelin S, is apoptotically active. Relevance of sialic acid modification. J. Biol. Chem., 279, 8577–8584.
Nixon, B., Lu, Q., Wassler, M.J., Foote, C.I., Ensslin, M.A., and Shur, B.D. (2001) Galactosyltransferase function during mammalian fertilization. Cells Tissues Organs, 168, 46–57.[CrossRef][ISI][Medline]
Oehninger, S., Coddington, C.C., Hodgen, G.D., and Seppala, M. (1995) Factors affecting fertilization: endometrial placental protein 14 reduces the capacity of human spermatozoa to bind to the human zona pellucida. Fertil. Steril., 63, 377–383.[ISI][Medline]
Okamoto, N., Uchida, A., Takakura, K., Kariya, Y., Kanzaki, H., Riittinen, L., Koistinen, R., Seppala, M., and Mori, T. (1991) Suppression by human placental protein 14 of natural killer cell activity. Am. J. Reprod. Immunol., 26, 137–142.
Pockley, A.G. and Bolton, A.E. (1989) Placental protein 14 (PP14) inhibits the synthesis of interleukin-2 and the release of soluble interleukin-2 receptors from phytohaemagglutinin-stimulated lymphocytes. Clin. Exp. Immunol., 77, 252–256.[ISI][Medline]
Pockley, A.G., Mowles, E.A., Stoker, R.J., Westwood, O.M., Chapman, M.G., and Bolton, A.E. (1988) Suppression of in vitro lymphocyte reactivity to phytohemagglutinin by placental protein 14. J. Reprod. Immunol., 13, 31–39.[CrossRef][ISI][Medline]
Powell, L.D., Sgroi, D., Sjoberg, E.R., Stamenkovic, I., and Varki, A. (1993) Natural ligands of the B cell adhesion molecule CD22 beta carry N-linked oligosaccharides with alpha-2,6-linked sialic acids that are required for recognition. J. Biol. Chem., 268, 7019–7027.
Rachmilewitz, J., Borovsky, Z., Riely, G.J., Miller, R., and Tykocinski, M.L. (2003) Negative regulation of T cell activation by placental protein 14 is mediated by the tyrosine phosphatase receptor CD45. J. Biol. Chem., 278, 14059–14065.
Rachmilewitz, J., Riely, G.J., Huang, J.H., Chen, A., and Tykocinski, M.L. (2001) A rheostatic mechanism for T-cell inhibition based on elevation of activation thresholds. Blood, 98, 3727–3732.
Rachmilewitz, J., Riely, G.J., and Tykocinski, M.L. (1999) Placental protein 14 functions as a direct T-cell inhibitor. Cell Immunol., 191, 26–33.[CrossRef][ISI][Medline]
Riely, G.J., Rachmilewitz, J., Koo, P.H., and Tykocinski, M.L. (2000) Alpha2-macroglobulin modulates the immunoregulatory function of the lipocalin placental protein 14. Biochem. J., 351, 503–508.
Riittinen, L., Julkunen, M., Seppala, M., Koistinen, R., and Huhtala, M.L. (1989) Purification and characterization of endometrial protein PP14 from mid-trimester amniotic fluid. Clin. Chim. Acta, 184, 19–29.[CrossRef][ISI][Medline]
Seppala, M. (2004) Advances in uterine protein research: reproduction and cancer. Int. J. Gynaecol. Obstet., 85, 105–118.[CrossRef][Medline]
Seppala, M., Taylor, R.N., Koistinen, H., Koistinen, R., and Milgrom, E. (2002) Glycodelin: a major lipocalin protein of the reproductive axis with diverse actions in cell recognition and differentiation. Endocr. Rev., 23, 401–430.
Skornicka, E.L., Kiyatkina, N., Weber, M.C., Tykocinski, M.L., and Koo, P.H. (2004) Pregnancy zone protein is a carrier and modulator of placental protein-14 in T-cell growth and cytokine production. Cell Immunol., 232, 144–156.[CrossRef][ISI][Medline]
Tse, J.Y., Chiu, P.C., Lee, K.F., Seppala, M., Koistinen, H., Koistinen, R., Yao, Y.Q., and Yeung, W.S. (2002) The synthesis and fate of glycodelin in human ovary during folliculogenesis. Mol. Hum. Reprod., 8, 142–148.
Tykocinski, M.L., Xiong, N., and Morrow, D.M. (1996) Platelet immunoregulatory factors. Stem Cells, 14 (Suppl. 1), 240–245.
Van Cong, N., Vaisse, C., Gross, M.S., Slim, R., Milgrom, E., and Bernheim, A. (1991) The human placental protein 14 (PP14) gene is localized on chromosome 9q34. Hum. Genet., 86, 515–518.[ISI][Medline]
Van den Nieuwenhof, I.M., Koistinen, H., Easton R.L., Koistinen R., Kamarainen M., Morris, H.R., Van Die, I., Seppala, M., Dell, A., and Van den Eijnden, D.H. (2000) Recombinant glycodelin carrying the same type of glycan structures as contraceptive glycodelin-A can be produced in human kidney 293 cells but not in Chinese hamster ovary cells. Eur. J. Biochem., 267, 4753–4762.[ISI][Medline]
Vigne, J.L., Hornung, D., Mueller, M.D., and Taylor, R.N. (2001) Purification and characterization of an immunomodulatory endometrial protein, glycodelin. J. Biol. Chem., 276, 17101–17105.
Woodworth, A. and Baenziger, J.U. (2001) The man/GalNAc-4-SO4-receptor has multiple specificities and functions. Results Probl. Cell Differ., 33, 123–138.[Medline]
Yaniv, E., Borovsky, Z., Mishan-Eisenberg, G., and Rachmilewitz, J. (2003) Placental protein 14 regulates selective B cell responses. Cell Immunol., 222, 156–163.[CrossRef][ISI][Medline]
Yao, Y.Q., Yeung, W.S., and Ho, P.C. (1996) The factors affecting sperm binding to the zona pellucida in the hemizona binding assay. Hum. Reprod., 11, 1516–1519.
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