Disease relevance of Hpse

• In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis [1].
• Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis [2].
• The role of heparanase in lymph node metastatic dissemination: dynamic contrast-enhanced MRI of Eb lymphoma in mice [3].
• The CAT-promoting activity of the early simian virus 40 promoter in plasmid pSV2 CAT is refractory to methylation by the Hpa II or Hha I DNA methyltransferase at 5' C-C-G-G 3' or 5' G-C-G-C 3' sequences, respectively, because this promoter lacks such sites [4].
• The polyoma mRNA's present in the cytoplasm of primary cultures of mouse kidney cells during lytic infection were characterized by sedimentation velocity analysis and by hybridization to polyoma DNA fragments generated by a specific endonuclease of Hemophilus parainfluenzae (Hpa II) [5].

High impact information on Hpse

• About 1% of the mouse genome is cleaved by Hpa II to give a discrete fraction on gels [6].
• S49 cells contain two copies of the MT-I gene; both alleles are heavily methylated but can be conveniently distinguished by the methylation status of a single Hpa II site [7].
• The extent of DNA methylation within the MT-I gene and its flanking regions was determined by comparing the cleavage patterns generated by the isoschizomeric restriction enzymes Hpa II and Msp I [8].
• To determine whether 5-azacytidine treatment changes the methylation pattern near the MT-I gene, we treated W7 cells with 5-azacytidine and selected inducible cells in 10 micro M cadmium. all of the Hpa II sites within the MT-I gene are unmethylated in these cadmium-resistant W7 cells [8].
• We conclude that methylation at Hpa II sites is replicated by these cultured cells but not with 100% fidelity [9].

Chemical compound and disease context of Hpse

• N-acetylated glycol-split species of heparin as well as siRNA heparanase gene silencing inhibit tumor metastasis and angiogenesis in experimental models [2].
• These data provide evidence that an endogenous, heat-stable inhibitor of cell surface degradative enzymes such as heparanase may play a role in hematogenous metastasis, and support the hypothesis that butanol extraction activates some of these surface enzymes by removing the endogenous inhibitors [10].
• Suramin. A potent inhibitor of melanoma heparanase and invasion [11].
• Nucleoplasm prepared from murine erythroleukemia cells was assayed from enzymatic activity which removes methyl groups from DNA methylated at the internal C of the sequence 5'-CCGG-3' (Hpa II sites) [12].
• We previously found that heparanase activity correlates with the lung colonization abilities of murine B16 melanoma cells and is inhibited by heparin [Nakajima, M., Irimura, T., Di Ferrante, N., & Nicolson, G. L. (1984) J. Biol. Chem. 259, 2283-2290] [13].

Biological context of Hpse

• By monitoring in vivo activation of luciferase reporter gene driven by heparanase promoter, we observed activation of heparanase gene transcription at a specific stage of the hair cycle [14].
• Degradation of heparan sulfate by heparanase enables cell movement through extracellular barriers and releases growth factors from extracellular matrix depots, making them bioavailable [14].
• For example, cell surface expression of heparanase elicits a firm cell adhesion, reflecting an involvement in cell-ECM interaction [2].
• Heparanase upregulation correlates with increased tumor vascularity and poor post-operative survival of cancer patients [2].
• Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals [2].

Anatomical context of Hpse

• Heparanase was produced by rat vibrissa bulge keratinocytes, closely related to a follicular stem cell population [14].
• Here, we demonstrate a highly coordinated temporospatial pattern of heparanase expression and enzymatic activity during hair follicle cycling [14].
• Here, we report that heparanase mRNA and protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet carcinogenesis [15].
• DESIGN: Comparison between mouse blastocysts obtained after 24-hour incubation of morulae with or without heparanase [16].
• On days 5 and 7 after the fracture, when mesenchymal cells proliferated and differentiated into chondrocytes, heparanase mRNA was detected in osteo(chondro)clasts and their precursors, but not in the inflammatory phase (day 3) [17].

Associations of Hpse with chemical compounds

• Drastic shortening of heparan sulfate chains was observed in heparanase-overproducing organs, such as liver and kidney [1].
• Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase [18].
• Experiments with the restriction enzyme Hpa II, which is sensitive to cytosine methylation in the sequence CCGG, demonstrated that the DNA synthesized in 5-aza-CR-treated cultures was maximally undermethylated 48 hr after treatment [19].
• The restriction enzymes Hpa II and Msp I both recognize the sequence 5'-CCGG (C, cytosine; G, guanine) [20].
• Both heparanase and beta-hexosaminidase, a mast cell granule enzyme, were released on degranulation of BMMC induced by the calcium ionophore A23187, or by exposure to IgE-Ag, suggesting that heparanase is localized in the cell granules [21].

Regulatory relationships of Hpse

• In heparanase-overexpressing transgenic mice, increased levels of heparanase enhanced active hair growth and enabled faster hair recovery after chemotherapy-induced alopecia [14].
• The metalloproteinase inhibitor 1,10-phenanthroline and the heparanase inhibitor heparin partially (30 to 50%) blocked extracellular matrix degradation [10].

Other interactions of Hpse

• MAIN OUTCOME MEASURE(S): Blastocysts were evaluated by heparanase immunostaining (n = 10), activity assay (n = 283), and transfer to foster mice uterine horns (n = 228) [16].
• Degradation of the ECM-HS by the mast cell heparanase and the associated release of HS-bound endothelial cell growth factors that are stored in ECM (Vlodavsky et al, Proc Natl Acad Sci USA 84:2292, 1987; Bashkin et al, Biochemistry 28:1737, 1989) may play a role in the proposed mast cell-mediated stimulation of neovascularization [21].
• The release of matrix-bound bFGF was independent of heparanase activity, since neither macrophage nor foam cells degraded 35SO4-labeled heparan sulfate proteoglycans [22].
• The results indicated that although N-sulfate and O-sulfate groups on glucosamine residues, and carboxyl groups on uronic acid residues, are important for heparanase inhibition, they are not essential for full activity [13].
• Heparanase secreted by the cells of HERS may contribute to root formation by degrading perlecan in the dental basement membrane [23].

Analytical, diagnostic and therapeutic context of Hpse

• The recombinant mouse heparanase protein was purified to homogeneity from cell lysates by a combination of Con-A affinity chromatography, heparin affinity chromatography, and size exclusion chromatography [24].
• The methylation status of Hpa II sites in these molecules was analyzed by Hpa II digestion of the genomic DNA isolated from blastocysts, followed by PCR amplification using appropriate primers [25].
• On the other hand, phi X174 replicative form DNA that was methylated in vitro at its C-C-G-G residues retains these methylations as shown by restriction enzyme analysis with Hpa II and Msp I to detect methylation at this specific site [26].
• The distribution of 5-methyl cytosine (5-MeC) residues in a highly repetitive sequence, mouse major satellite, was examined in germinal versus somatic DNAs by digestion with the methylation sensitive isoschizomers Msp I and Hpa II and Southern blot analysis, using a cloned satellite probe [27].
• Comparison of heparanase expression in situ and in corresponding tumor cell cultures in vitro or after xenotransplantation into NOD/Scid mice revealed that heparanase expression was regulated in vivo [28].

References