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Keywords:

  • serglycin;
  • proteoglycan;
  • immunity;
  • hemostasis;
  • reproduction;
  • cancer;
  • inflammatory diseases;
  • platelet disorders

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SERGLYCIN GENE
  5. PHYSIOLOGICAL ROLES OF SERGLYCIN
  6. SERGLYCIN IN DISEASES
  7. LITERATURE CITED

Serglycin is a multifunctional molecule and one of the first proteoglycans to be cloned. In this manuscript, we examine the physiological roles of serglycin in immunity, hemostasis, cell growth, apoptosis, and reproduction. In addition, we review recent studies on the involvement of serglycin in various pathological conditions, including cancer, inflammatory diseases, and platelet disorders. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SERGLYCIN GENE
  5. PHYSIOLOGICAL ROLES OF SERGLYCIN
  6. SERGLYCIN IN DISEASES
  7. LITERATURE CITED

Proteoglycans consist of a core protein with one or more attached glycosaminoglycan chains (Yip et al., 2006; Varki et al., 2008). Besides structural roles in the extracellular matrix, these molecules have gained recognition for their functions in normal physiology and in various disease states (Theocharis et al., 2010). Furthermore, proteoglycans are promising therapeutic targets and prognostic markers in cancer and other disorders. One of the first proteoglycans that was cloned is serglycin (Bourdon et al., 1985). However, the roles of this molecule in health and in different diseases have yet to be explored extensively.

Serglycin was first discovered as a secretory product of a rat yolk sac tumor (Oldberg et al., 1981). It is an intracellular proteoglycan, but can also be secreted and incorporated into the extracellular matrix (Schick et al., 2001a; Kolset and Tveit, 2008). The core protein is 17.6 kDa in size, and contains a 16-amino acid serine/glycine repeat region to which glycosaminoglycan chains are attached (Grujic et al., 2005; Theocharis et al., 2006; Schick, 2010). Serglycin is mainly expressed in cells in the hematopoietic lineage, such as neutrophils, lymphocytes, monocytes, macrophages, platelets, megakaryocytes, and mast cells (Elliott et al., 1993; Schick and Jacoby, 1995; Abrink et al., 2004; Niemann et al., 2004; Zernichow et al., 2006; Kolset and Zernichow, 2008; Woulfe et al., 2008). It has thus also been dubbed a “hematopoietic proteoglycan.” In addition, as extensively reviewed by Kolset and Pejler (2011), serglycin is a dominant proteoglycan in immune cells, where it plays major roles in intracellular storage of compounds for secretion, homeostasis of secretory granules, apoptosis, responses to infection, and blood coagulation. Studies have also shown that serglycin is present in endothelial cells, uterine decidua, and embryonic stem cells (Keith Ho et al., 2001; Schick et al., 2001a, 2003).

Glycosaminoglycans that may be attached to serglycin include heparan sulfate, heparin, and chondroitin sulfate (Toyama-Sorimachi et al., 1995; Kolset and Tveit, 2008). The composition and extend of sulfation of glycosaminoglycan chains differ among cell types, and are vital determinants of serglycin function (Toyama-Sorimachi et al., 1995; Kolset and Tveit, 2008). This is evidenced by the types of glycosaminoglycan chains in various cells and under varying conditions. Heparin, the most highly sulfated glycosaminoglycan chain in serglycin, is found only in connective tissue mast cells (Kolset and Pejler, 2011). Intriguingly, serglycin from mucosal tissue mast cells (which have similar but nonidentical functions to connective tissue mast cells) contains chondroitin-4,6-disulfate chains (Kolset and Tveit, 2008). Activated monocytes and macrophages predominantly contain highly sulfated chondroitin-4,6-disulfate molecules (Uhlin-Hansen et al., 1989). In contrast, quiescent monocytes express chondroitin-4-sulfate, which has fewer sulfate groups. The core protein and attached glycosaminoglycan chains are both important for the biological activity of serglycin. Toyama-Sorimachi et al. (1995) reported that CD44 binds to serglycin through the chondroitin-4-sulfate side chains on the latter molecule. Elimination of chondroitin-4-sulfate chains from serglycin abolished this binding. Furthermore, CD44 does not bind to free chondroitin-4-sulfate molecules.

The synthesis of serglycin is highly dependent on the cell type and external stimulation (Schick et al., 2003). Further, the amount of serglycin mRNA present is often inversely correlated to the size of the glycosaminoglycan chain, and may thus affect its function (Schick et al., 2001b). In nonstimulated macrophages, most of the synthesized serglycin is routed to the degradation pathway. However, when these cells are stimulated with lipopolysaccharide, the synthesized serglycin is sorted to the secretory pathway (Fig. 1) (Uhlin-Hansen et al., 1993). Glycosaminoglycan chains play an important role in cellular differentiation. U937 cells that were differentiated using phorbol-12-myristate-13-acetate (PMA), retinoic acid, or 1α,25-dihydroxycholecalciferol contain glycosaminoglycan chains of distinct sizes (Kulseth et al., 1998). Glycosaminoglycans have been reported to regulate intracellular sorting of serglycin to secretory vesicles in rat pancreatic acinar cells (Biederbick et al., 2003).

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Figure 1. Synthesis of serglycin in macrophages. In nonstimulated macrophages, most of the synthesized serglycin is degraded. In contrast, the molecules are sorted to the secretory pathway in macrophages stimulated with lipopolysaccharide.

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SERGLYCIN GENE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SERGLYCIN GENE
  5. PHYSIOLOGICAL ROLES OF SERGLYCIN
  6. SERGLYCIN IN DISEASES
  7. LITERATURE CITED

The serglycin gene is located on chromosome 10q.22.1 (Stevens et al., 1988; Mattei et al., 1989). It has 1.8 kb of 5′-flanking DNA, 1.2 kb of three exons, 8.8 kb in Intron 1, and 6.7 kb in Intron 2 (Humphries et al., 1992). The first exon (Fig. 2) encodes the 5′-untranslated mRNA region and the hydrophobic signal peptide of the translated protein (Nicodemus et al., 1990; Humphries et al., 1992). The second exon codes for the amino terminus of the protein after the signal sequence has been cleaved off during translation in the endoplasmic reticulum, while the third exon encodes the glycosaminoglycan attachment region and the C-terminus (Nicodemus et al., 1990; Humphries et al., 1992).

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Figure 2. Structure of the serglycin protein.

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A commonly conserved 70 bp sequence known as the Donehower element is found in the non-coding region of the 8.8 kb intron (Donehower et al., 1989; Humphries et al., 1992). However, another common DNA sequence, the Kpn sequence, is not present (Kole et al., 1983; Humphries et al., 1992). In addition, the human serglycin gene contains an unusually high number of Alu element/kb, with nineteen and two Alu elements being located in the introns and 5′-flanking DNA, respectively (Humphries et al., 1992; Castronuevo et al., 2003).

The (−80)ets and (−70)CRE sites located at the 5′-flanking region are the most critical regulatory elements for serglycin gene expression. Additionally, the expression of serglycin after treatment of human erythroleukemia, CHRF 288-11, and promyelocytic HL-60 cells with PMA and dibutyryl cyclic AMP are determined by the CRE site (Schick et al., 2001b). The cis- and trans-acting elements in the 5′-UTR also regulate serglycin gene expression (Kolset and Tveit, 2008).

Expression of serglycin is regulated by the methylation status of the serglycin gene. Humphries et al. (1992) showed that the amount of serglycin transcript is inversely related to methylation of the 8.8 kb intron. In cells with abundant serglycin transcripts, methylation of the 8.8 kb intron is diminished (Humphries et al., 1992). Another mechanism for regulating the expression of serglycin involves the position of DNaseI hypersensitivity sites (DHSS) within the serglycin gene (Castronuevo et al., 2003). DHSS are short chromatin regions with perturbed nucleosome formation that have increased sensitivity to factors interacting with DNA (Cockerill, 2000). Interestingly, some DHSS are found to be in close proximity to the high amounts of Alu repeats in Intron 1 (Castronuevo et al., 2003). Although the association between DHSS and these Alu regions has not been directly established, reports have shown that insertions and recombination events involving Alu elements could be responsible for genetic defects, which subsequently lead to human diseases such as cancer (Deininger and Batzer, 1999).

Of interest, an mRNA isoform of serglycin that codes for the core protein without Exon 2 is present in neutrophils, and found in small proportion in HL-60 cells (Stellrecht et al., 1991; Kolset and Tveit, 2008). The detection of this isoform in HL-60 cells could be attributed to differential expression of serglycin during the maturation of promyelocytes to form segmented neutrophils.

PHYSIOLOGICAL ROLES OF SERGLYCIN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SERGLYCIN GENE
  5. PHYSIOLOGICAL ROLES OF SERGLYCIN
  6. SERGLYCIN IN DISEASES
  7. LITERATURE CITED

Serglycin has been extensively studied in the immune system, where it is expressed and essential to the functions of mast cells, cytotoxic T-lymphocytes (CTL), monocytes, and neutrophils. The maturation of mast cells is closely related to the expression of serglycin, as well as sulfotransferases such as chondroitin-4-sulfotransferase-1 and GalNAc(4S)-6-O-sulfotransferase which produce highly sulfated chondroitin sulfate chains attached to serglycin (Duelli et al., 2009). Serglycin also regulates the integrity of secretory granules, and the storage and release of secretory granule proteases, serotonin, and histamine from these cells (Abrink et al., 2004; Henningsson et al., 2006; Braga et al., 2007; Ringvall et al., 2008). Deterioration of these granules and release of the stored proteases may lead to proteolytic events, which activate proapoptotic compounds in the cytosol and induce apoptosis of the mast cells. Mast cells that lack serglycin showed decreased sensitivity to this form of apoptosis and underwent death by necrosis rather than apoptosis. Furthermore, serglycin was reported to affect apoptosis by regulating the activation of caspase-3 and processing of Bid (Melo et al., 2011b).

In CTL, serglycin plays a similar role in influencing the storage and retention of granzyme B, a serine protease involved in apoptosis (Lord et al., 2003; Grujic et al., 2005, 2008). In addition, it is involved in inflammation through regulation of chemokine growth related oncogene α (GROα) and platelet derived growth factor (Cuenca et al., 1992; Heldin, 1992; Woulfe et al., 2008; Meen et al., 2011).

It is believed that serglycin is the only proteoglycan found in platelets and thus plays an inherent role in hemostasis (Woulfe et al., 2008). Platelets from serglycin knockout mice have altered morphology plus defective platelet factor-4 (PF4) and β-thromboglobulin, which are critical for platelet activation and hemostasis (Kaplan and Owen, 1981; Eisman et al., 1990; Woulfe et al., 2008). Furthermore, there is a decrease in adenosine triphosphate and serotonin release. Reduced secretion of these dense granule contents and the defect in PF4 may hinder the activation of αIIbβ3, a major platelet membrane receptor that binds to fibrinogen for platelet aggregation. Indeed, platelets from serglycin null (SG−/−) mice have a defective aggregation response and a higher tendency to disaggregrate (Woulfe et al., 2008). The distribution of serglycin in human umbilical vein endothelial cells is correlated with tissue plasminogen activator, which is important for breaking down blood clots (Schick et al., 2001a).

In addition, serglycin may have some roles in the reproductive system. The molecule is expressed in undifferentiated embryonic stem cells and embryoid bodies, and hypothesized to modulate interactions between the inner cell mass and the trophectoderm in the blastocyst (Keith Ho et al., 2001). Serglycin could affect signaling within the decidua, or between the placenta and the decidua (Schick, 2010). Further, serglycin is believed to be important for uterine decidual function and fetal development, including the formation of blood cells, suggesting that the molecule may play a role in fertility (Keith Ho et al., 2001; Schick, 2010). Indeed, a rise in endometrial CD16(−) natural killer cells post ovulation has been shown to be critical for pregnancy (Kitaya et al., 2007). Serglycin may be involved in extravasation of peripheral blood natural killer cells into the endometrium (Santoni et al., 2008; Yasuo et al., 2008).

SERGLYCIN IN DISEASES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SERGLYCIN GENE
  5. PHYSIOLOGICAL ROLES OF SERGLYCIN
  6. SERGLYCIN IN DISEASES
  7. LITERATURE CITED

Studies have reported that serglycin plays a major role in various diseases, including cancer and inflammatory disorders.

Serglycin in Cancer

Serglycin has been shown to be a biomarker of acute myeloid leukemia, and can be used to distinguish this disease from acute lymphocytic leukemia and Philadelphia chromosome negative chronic myeloproliferative disorders (Niemann et al., 2007b). It is found in various human leukemia cell lines (Maillet et al., 1992; Schick and Jacoby, 1995). Serglycin is highly expressed in U937, a methotrexate- and vincristine-resistant hematopoietic tumor cell line, suggesting that it may confer resistance to chemotherapeutic drugs (Beyer-Sehlmeyer et al., 1999). In multiple myeloma, serglycin enables tumor cells to evade immunotherapy by preventing complement-dependent cytotoxicity (Skliris et al., 2011). Serglycin binds to C1q and mannose-binding lectin through its chondroitin sulfate chains and prevents the activation of complement and opsonization. Interestingly, inhibition of this pathway appears to be dependent on the sulfation pattern of chondroitin sulfate and the overall negative charge of the glycosaminoglycan chain. Chondroitin sulfate secreted by multiple myeloma cells contains mostly 4-sulfated disaccharides (Skliris et al., 2011). Further, serglycin aids in the adhesion of myeloma cells to the bone marrow extracellular matrix, which is critical for tumor spread and disease outcome (Theocharis et al., 2006).

Invasive nasopharyngeal carcinoma cells secrete higher levels of serglycin, which may be involved in metastasis of this cancer (Li et al., 2011). Serglycin expression has been correlated with adverse prognosis in nasopharyngeal cancer patients, and the molecule could be a suitable therapeutic target (Li et al., 2011; Li and Qian, 2011).

Serglycin and the Immune System

The various roles of serglycin in immune cells have led to studies on the involvement of serglycin in immunity, inflammatory disorders, and rheumatic disorders. In adaptive immunity, potent CTL are generated in response to infection followed by contraction to memory cells (Badovinac et al., 2002). This contraction was delayed when mice lacking serglycin were infected with lymphocytic choriomeningitis viruses (Grujic et al., 2008). In addition, serglycin is essential for proper localization of neutrophil elastase, a major component of the azurophil granule in neutrophils (Wong et al., 1999; Niemann et al., 2007a). Neutrophil elastase is a serine protease that is involved in inflammation (Rodeberg et al., 1997; Korkmaz et al., 2008). Mislocalization of this protease in serglycin-deficient mice injected with Klebsiella pneumonia led to an increase in bacterial virulence (Niemann et al., 2007a).

In rheumatic diseases, synovial fluid and peripheral blood samples collected from patients showed higher levels of serglycin in CD14+ and CD2+ mononuclear cells (Omtvedt et al., 2001). CD14+ cells are involved in arthropathy, and CD2+ cells activates T-lymphocytes in rheumatic diseases (Guckel et al., 1991; Hoffmann et al., 1997; Li et al., 2004). In dermatomyositis, cutaneous vessels have increased expression of serglycin (Kim and Werth, 2011). In addition, serglycin expression was increased after exposure to radiation to the skin dermis, suggesting that serglycin may participate in dermal inflammation (Werth et al., 2011). The prominent role of serglycin in inflammation has prompted researchers to exploit it for treating allergy diseases. Melo et al. (2011a) suggested the use of lysosomotropic agents to release proteases and serglycin to promote apoptosis of mast cells. Another strategy is based on exploiting the dependence on serglycin for storage of serotonin and histamine in mast cell secretory granules (Ringvall et al., 2008).

Serglycin in Hemostasis, Thrombosis, and Atherosclerosis

Since serglycin is important for platelet function, it is not unexpected to find that serglycin is involved in platelet-associated disorders. One example is the gray platelet syndrome, which is a congenital bleeding disorder with α-granule-deficient platelets (Nurden and Nurden, 2007). An animal model of this disease is the Wistar Furth hereditary macrothrombocytopenic rat (Jackson et al., 1991). Scroll-like membranous inclusions can be found in these rats as well as in serglycin-knockout mice (White, 2004; Woulfe et al., 2008). Another feature that is seen in both patients with gray platelet syndrome and serglycin-deficient mice is neutrophil emperipolesis, where an intact neutrophil is found in a megakaryocyte (Woulfe et al., 2008). Schick et al. (1997) postulated that the abnormal α-granules in Wistar Furth hereditary macrothrombocytopenic rats are due to unusually small serglycin in the platelets of these animals. This leads to atypical packaging of the granules' components and their premature release, thereby altering the bone marrow environment and resulting in myelofibrosis (Schick et al., 1997).

Serglycin-deficient mice have been found to have impaired hemostasis due to a defective thrombosis response and easily disaggregated platelets (Woulfe et al., 2008). It may affect atherosclerosis and the progression of coronary arterial disease through its effect on GROα (Bechara et al., 2007; Breland et al., 2008; Meen et al., 2011). It has been suggested that the absence of serglycin-delivered PF4 could prevent atherosclerotic plaque formation, as PF4 is involved in atherosclerosis (Pitsilos et al., 2003; Sachais et al., 2007; Schick, 2010).

In summary, serglycin is a multifunctional proteoglycan with physiological roles in immunity, hemostasis, cell growth, apoptosis, and reproduction. Recent studies have also shown that the molecule is involved in various diseases, including cancer and inflammatory disorders (Fig. 3).

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Figure 3. Summary of the involvement of serglycin in various conditions.

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LITERATURE CITED

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SERGLYCIN GENE
  5. PHYSIOLOGICAL ROLES OF SERGLYCIN
  6. SERGLYCIN IN DISEASES
  7. LITERATURE CITED
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