Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.36 (hyaluronidase)
 4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of the adhesion molecule CD44 in the development of NK cells was analyzed in a mouse long-term bone marrow culture system. After 4 wk of culture (day 0), recombinant human IL-2 was added and 13 days later the cells generated were shown to have substantial cytotoxic activity against YAC-1 and to be enriched for NK cells, as assessed for NK-1.1 phenotype by flow cytometric analysis. Physical separation between stroma and precursors partially inhibited proliferation and, consequently, a lower number of cytotoxic cells were produced. Similar results were obtained when an anti-CD44 mAb was added together with IL-2 at day 0. The disruption of hyaluronic acid (HA), one of the ligands of CD44, by hyaluronidase or the competition for the binding of CD44 by soluble HA added with IL-2 on day 0 inhibited both proliferation and development of cytotoxicity to a greater degree than did anti-CD44. These results indicate that interaction of CD44 with HA plays an important role in the development of pre-NK cells into cytotoxic effector cells.
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PMID:Role of CD44 in the development of natural killer cells from precursors in long-term cultures of mouse bone marrow. 751 28

We report herein identification of a novel ligand for CD44, a cell surface glycoprotein implicated in tumor metastasis, lymphocyte differentiation and homing. A mouse T cell line CTLL-2 transfected with cDNA encoding a hemopoietic form of mouse CD44 exhibited a new self-adhesive phenotype, forming large aggregates. The aggregation was blocked by anti-CD44 mAb but little affected by hyaluronidase, indicating the involvement of CD44 and its non-hyaluronate ligand in the cell aggregation. The ability to induce CD44-dependent aggregation was observed in culture supernatants of CTLL-2 and its CD44 transfectants. Immunoprecipitation analysis using a CD44-Ig chimeric molecule indicated that CTLL-2 and its transfectants synthesized a macromolecule (gp600) which bound specifically to CD44. gp600 was readily labeled with radioactive sulfate and treatment of gp600 with chondroitinase ABC or AC II generated a lower molecular weight species (18-22 kDa), suggesting that gp600 consists of a small core protein heavily modified with chondroitin sulfate glycosaminoglycan side chains. However, when binding of CD44 was tested in vitro to chondroitinase-sensitive purified glycosaminoglycans, such as chondroitin-4-sulfate, chondroitin-6-sulfate and dermatan sulfate, no binding was demonstrable, suggesting either that a novel type of chondroitinase-sensitive glycosaminoglycan is recognized by CD44 or that association of the glycosaminoglycan with a core protein is required for recognition by CD44.
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PMID:A novel ligand for CD44 is sulfated proteoglycan. 751 79

Hyaluronan-binding sites were demonstrated on the cell surface of three malignant mesothelioma cell lines derived from human tumors using either [3H]hyaluronan or fluorescein-tagged hyaluronan. No hyaluronan-binding activity was observed on normal human mesothelial cells. The absence of hyaluronan receptors on normal human mesothelial cells was not due to a down-regulation by endogenously synthesized hyaluronan, since no binding sites appeared when the cells were cultured under conditions known to suppress hyaluronan synthesis (in starvation medium containing either hydrocortisone or n-butyrate) or to degrade endogenously synthesized hyaluronan (in the presence of Streptomyces or testicular hyaluronidase). The binding of [3H]hyaluronan on mesothelioma cells could be partially inhibited by prior incubation of the cells with trypsin, indicating that the hyaluronan-binding site is a protein. The binding sites on human malignant mesothelioma cells were shown to be saturable with about 54,000 hyaluronan molecules (M(r) 1.4 x 10(6)) bound per cell with a Kd of 0.3 x 10(-9) M. The binding was specific for hyaluronan inasmuch as a number of other macromolecules gave negligible inhibition of the binding. High molecular weight preparations of hyaluronan inhibited the binding more effectively than low molecular weight preparations; hyaluronan oligosaccharides down to a length of six monosaccharide units showed competing activity. The hyaluronan receptor appeared to be related to CD44 (a cell surface glycoprotein previously suggested to function as a hyaluronan receptor) since Hermes-1 monoclonal antibodies which inhibit the binding of hyaluronan to CD44 blocked a major part of the binding of hyaluronan to the mesothelioma cells. However, there was no strict correlation between the hyaluronan-binding activity on the mesothelioma cell lines tested and the levels of CD44 molecules on their cell surface, suggesting that only a subfraction of the CD44 molecules bound hyaluronan or that other hyaluronan-binding proteins also exist on those cells. The presence of hyaluronan receptors on mesothelioma cells, but not on their normal counterparts, may be of importance for the migration of the transformed cells in hyaluronan-enriched matrices and for their ability to form metastases.
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PMID:Hyaluronan receptors are expressed on human malignant mesothelioma cells but not on normal mesothelial cells. 751 23

Asthma is a disease of airway inflammation and hyperreactivity that is associated with a lymphocytic infiltrate in the bronchial submucosa. The interactions between infiltrating T lymphocytes with cellular and extracellular matrix components of the airway and the consequences of these interactions have not been defined. We demonstrate the constitutive expression of CD44 on human airway smooth muscle (ASM) cells in culture as well as in human bronchial tissue transplanted into severe combined immunodeficient mice. In contrast, basal levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression are minimal but are induced on ASM by inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha). Activated, but not resting T cells, adhere to cultured ASM; stimulation of the ASM with TNF-alpha enhanced this adhesion. Adhesion was partially blocked by monoclonal antibodies (mAb) specific for lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) on T cells and ICAM-1 and VCAM-1 on ASM cells. The observed integrin-independent adhesion was mediated by CD44/hyaluronate interactions as it was inhibited by anti-CD44 mAb 5F12 and by hyaluronidase. Furthermore, the adhesion of activated T lymphocytes induced DNA synthesis in growth-arrested ASM cells. Thus, the interaction between T cells and ASM may provide insight into the mechanisms that induce bronchial inflammation and possibly ASM cell hyperplasia seen in asthma.
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PMID:T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis. 752 Apr 73

We have isolated and characterized the human cardiac mast cell (CMC) and compared this novel mast cell (MC type with MC obtained from uterus, skin, and lung. Heart tissue was obtained from 14 patients with cardiomyopathy (CMP, heart transplantation). CMC were isolated by enzymatic digestion using collagenase, pronase-E, hyaluronidase, and DNAse. Substantial amounts of CMC (0.5% to 1.5% of isolated cells) were found in the atrial appendages but not in ventricular digests or other sites of the heart (< 0.1%). In situ staining of atrial tissue revealed the presence of CMC in the myocardium (2.16 +/- 0.7 MC/mm2), endocardium (2.24 +/- 0.9 MC/mm2), and epicardium. As assessed by combined toluidine blue/immunofluorescence staining with monoclonal antibodies (MoAbs), isolated CMC expressed surface IgE, the receptor for stem cell factor (c-kit receptor/CD117), the p24 antigen (CD9), the Pgp-1 homing receptor (CD44), the pan leukocyte antigen (CD45), and the ICAM-1 antigen (CD54). CMC were not recognized by MoAbs to lymphocyte function associated antigen 2 (LFA-2; CD2), T-cell receptor (TcR; CD3), T4 antigen (CD4), LFA-1 alpha-chain (CD11a), C3biR alpha-chain (CD11b), CR4 alpha-chain (CD11c), LPS-R related Ag (CD14), 3-FAL/x-hapten (CD15), Fc gamma RIII (CD16), lactosylceramid (CDw17), the B-cell antigen CD19, or CR1 (CD35). In situ expression of leukocyte antigens on CMC was demonstrable by indirect immunoperoxidase staining technique and double-labeling immunohistochemistry. Almost all CMC (90%) reacted with MoAbs against tryptase and chymase and thus were MCTC. Cardiac mast cells were also stained by the heparin-binding dye Berberine sulfate and expressed measurable amounts of histamine (4.6 +/- 1.4 pg per cell). Cross linking of either IgE receptor or SCF receptor (c-kit) on CMC resulted in histamine secretion (non-specific release: < 6% of total histamine, alpha IgE induced: 12% to 52%; SCF-induced release: 9% to 18%), whereas neither substance P (a skin MC agonist) nor the basophil agonist FMLP showed an effect on CMC. Together, the CMC is an MCTC primarily located in the appendage of the atrium. This novel type of MC exhibits surface membrane antigen and functional properties similar to those of lung and uterus MC.
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PMID:The human cardiac mast cell: localization, isolation, phenotype, and functional characterization. 752 50

We have identified a novel ligand for CD44, a cell surface glycoprotein implicated in tumor metastasis and lymphocyte homing. When the mouse T cell line CTLL-2 was transfected with cDNA encoding a hemopoietic form of mouse CD44, CTLL-2 cells exhibited a new self-adhesive phenotype, forming large aggregates. The aggregation was blocked by neutralizing anti CD44 monoclonal antibody but unaffected by hyaluronidase, indicating the involvement of CD44 and its non-hyaluronate ligand in the cell aggregation. The ability to induce CD44-dependent aggregation was found in culture supernatants of CTLL-2 and its CD44 transfectants. The use of CD44-immunoglobulin chimeric protein revealed that CTLL-2 and its transfectants synthesized a large-molecular weight protein (gp600) which bound specifically to CD44. The gp600 was readily labeled with radioactive sulfate, and treatment of gp600 with chondroitinase ABC or ACII generated a lower molecular weight species (18-22 kDa), suggesting that gp600 consists of a small core protein with chondroitin sulfate glycosaminoglycan side chains. However, binding of CD44 to glycosaminoglycans such as chondroitin 4-sulfate, chondroitin 6-sulfate, and dermatan sulfate was undetectable, suggesting either that a novel chondroitin-type glycosaminoglycan is recognized by CD44 or that a particular configuration of the glycosaminoglycan is required for recognition by CD44.
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PMID:A sulfated proteoglycan as a novel ligand for CD44. 2292 40

Similar to activated T cells, LB T cell lymphoma expresses the CD44 cell surface Ag. In addition, the vast majority of LB cells also express the beta 2 (CD18) and alpha L (CD11a) chains of LFA-1 integrin. In view of the finding that anti-CD18 mAb blocked spleen, but not lymph node invasion by LB cells inoculated s.c. into BALB/c mice, we tested the ability of anti-CD44 mAb (IM 7.8.1) to block the infiltration of LB cells into the lymph nodes. We found that, as opposed to anti-CD18 mAb, anti-CD44 mAb, as well as its F(ab')2 or Fab fragment, prevented lymph node infiltration but had no effect on spleen invasion. This conclusion was based on histologic examination and [3H]thymidine incorporation into proliferating LB cells invading the lymphoid organs. Histologic analysis further demonstrated that LB cells invade the lymph node via the afferent lymphatics. The surface expression of CD44 molecules on LB cells was enhanced after PMA activation. PMA activation also enabled in vitro binding of the lymphoma to hyaluronic acid (HA), a known ligand of CD44. Because anti-CD44 mAb, its F(ab')2 or Fab fragment, and hyaluronidase blocked this binding, we also tested the ability of the enzyme to inhibit lymph node invasion by LB cells. We established through histologic examination and [3H]thymidine incorporation that hyaluronidase protected the lymph node, but not the spleen, from invasion by the lymphoma.
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PMID:Lymph node (but not spleen) invasion by murine lymphoma is both CD44- and hyaluronate-dependent. 753 6

Although binding of peanut agglutinin (PNA) to keratinocytes is often used as a marker of terminal differentiation, the identity of the PNA-binding glycoproteins has been unclear. We now show that an antiserum raised against the glycoproteins recognises isoforms of CD44, the most abundant of which could be labelled with [35S]sulphate, indicating the presence of glycosaminoglycan side chains. RT-PCR analysis showed that keratinocytes expressed at least 5 forms of CD44 containing different numbers of exons from the variable region of the extracellular domain and also expressed the standard 'haemopoietic' form of CD44 which lacks the variable exons. Standard and variant isoforms of CD44 were expressed both by proliferating keratinocytes and cells undergoing terminal differentiation, although the level of CD44 mRNAs decreased when keratinocytes were placed in suspension to induce differentiation. The role of CD44 in intercellular adhesion was investigated by plating keratinocytes onto a rat pancreatic carcinoma line transfected with different CD44 isoforms. Keratinocyte adhesion to transfectants expressing variant exons 4-7 was greater than to cells expressing standard CD44 and could be inhibited with hyaluronan or digestion with hyaluronidase. These observations confirm earlier predictions that the PNA-binding glycoproteins of keratinocytes play a role in intercellular adhesion.
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PMID:CD44 is the major peanut lectin-binding glycoprotein of human epidermal keratinocytes and plays a role in intercellular adhesion. 754 99

The adhesion to mesothelial monolayers of eight cultured ovarian tumour cell lines was studied in multiwell plates as a model for some of the interactions of ovarian cancer in the peritoneal cavity. When only the upper half of the conditioned medium (CM) from a confluent mesothelial cell culture was aspirated, the adhesion of the tumour cells was low (3.5%-36%). When the medium was removed completely the adhesion increased. The tumour cell lines showing the greatest enhancement of adhesion were those which had previously been shown to express the highest amounts of CD44. By adding erythrocyte suspensions to mesothelial cells it was shown that there was a pericellular coat around the mesothelial cells that could be destroyed by aspirating the medium, or by treating the medium with hyaluronidase (Hase). Treatment of the CM with Hase also considerably increased tumour cell adhesion. Furthermore, CM was shown to contain high amounts of hyaluronic acid (HA). HA blocked adhesion in the absence of CM, but the effect was not as large as that produced by the pericellular coat. It is proposed that pericellular HA produced by mesothelial cells has an important role in the invasion of ovarian tumour cells in the peritoneal cavity.
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PMID:Hyaluronic acid secreted by mesothelial cells: a natural barrier to ovarian cancer cell adhesion. 764 21

Hyaluronan was localized in postimplantation mouse embryos using CD44, the principal hyaluronan receptor. The specificity of CD44 receptor-globulin labelling was confirmed using Streptomyces hyaluronidase, anti-chondroitin sulfate antibody, and other receptor globulins. Our major findings are summarized as follows: 1. Implantation of the blastocyst into the uterine wall triggers a rapid loss of hyaluronan from the extracellular matrix of decidual cells on the anti-mesometrial side of the uterus. 2. Hyaluronan appears early in development in the yolk cavity, and the basement membranes of primitive ectoderm and primitive endoderm. 3. During gastrulation, mesodermal cells enter a hyaluronan-rich environment, but lack a pericellular hyaluronan coat themselves. 4. In limb bud embryos, hyaluronan is present throughout the cranial mesenchyme, but is generally not present in the branchial bars, somites, or limb buds. 5. At mid-gestation, hyaluronan is present in the axial skeleton, craniofacial mesenchyme, endocardial cushions of the heart, smooth muscle of the gastrointestinal tract, and connective tissue throughout the body. The pattern of hyaluronan expression in the day 13 fetus is nearly identical to the published distribution of transforming growth factor beta (TGF beta), suggesting a close functional relationship between these molecules. Together, the results suggest that hyaluronan is involved in the formation of early mesoderm, differentiation of craniofacial mesenchyme, and morphogenesis of the axial skeleton.
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PMID:Localization of hyaluronan in mouse embryos during implantation, gastrulation and organogenesis. 769 85


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