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Gene Review

Hpse  -  heparanase

Mus musculus

Synonyms: Endo-glucoronidase, HSE1, Heparanase, Hpa, Hpr1
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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


Regulatory relationships of Hpse


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


  1. In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis. Li, J.P., Galvis, M.L., Gong, F., Zhang, X., Zcharia, E., Metzger, S., Vlodavsky, I., Kisilevsky, R., Lindahl, U. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Ilan, N., Elkin, M., Vlodavsky, I. Int. J. Biochem. Cell Biol. (2006) [Pubmed]
  3. The role of heparanase in lymph node metastatic dissemination: dynamic contrast-enhanced MRI of Eb lymphoma in mice. Dafni, H., Cohen, B., Ziv, K., Israely, T., Goldshmidt, O., Nevo, N., Harmelin, A., Vlodavsky, I., Neeman, M. Neoplasia (2005) [Pubmed]
  4. Expression of the chloramphenicol acetyltransferase gene in mammalian cells under the control of adenovirus type 12 promoters: effect of promoter methylation on gene expression. Kruczek, I., Doerfler, W. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  5. Mapping of the three species of polyoma mRNA. Türler, H., Salomon, C., Allet, B., Weil, R. Proc. Natl. Acad. Sci. U.S.A. (1976) [Pubmed]
  6. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Bird, A., Taggart, M., Frommer, M., Miller, O.J., Macleod, D. Cell (1985) [Pubmed]
  7. Ultraviolet radiation-induced metallothionein-I gene activation is associated with extensive DNA demethylation. Lieberman, M.W., Beach, L.R., Palmiter, R.D. Cell (1983) [Pubmed]
  8. DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells. Compere, S.J., Palmiter, R.D. Cell (1981) [Pubmed]
  9. The somatic replication of DNA methylation. Wigler, M., Levy, D., Perucho, M. Cell (1981) [Pubmed]
  10. Inhibition of experimental metastasis and extracellular matrix degradation by butanol extracts from B16-F1 murine melanoma. Keren, Z., Leland, F., Nakajima, M., LeGrue, S.J. Cancer Res. (1989) [Pubmed]
  11. Suramin. A potent inhibitor of melanoma heparanase and invasion. Nakajima, M., DeChavigny, A., Johnson, C.E., Hamada, J., Stein, C.A., Nicolson, G.L. J. Biol. Chem. (1991) [Pubmed]
  12. Presence of a DNA demethylating activity in the nucleus of murine erythroleukemic cells. Gjerset, R.A., Martin, D.W. J. Biol. Chem. (1982) [Pubmed]
  13. Chemically modified heparins as inhibitors of heparan sulfate specific endo-beta-glucuronidase (heparanase) of metastatic melanoma cells. Irimura, T., Nakajima, M., Nicolson, G.L. Biochemistry (1986) [Pubmed]
  14. Heparanase regulates murine hair growth. Zcharia, E., Philp, D., Edovitsky, E., Aingorn, H., Metzger, S., Kleinman, H.K., Vlodavsky, I., Elkin, M. Am. J. Pathol. (2005) [Pubmed]
  15. A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Joyce, J.A., Freeman, C., Meyer-Morse, N., Parish, C.R., Hanahan, D. Oncogene (2005) [Pubmed]
  16. Heparanase improves mouse embryo implantation. Revel, A., Helman, A., Koler, M., Shushan, A., Goldshmidt, O., Zcharia, E., Aingorn, H., Vlodavsky, I. Fertil. Steril. (2005) [Pubmed]
  17. Heparanase mRNA expression during fracture repair in mice. Saijo, M., Kitazawa, R., Nakajima, M., Kurosaka, M., Maeda, S., Kitazawa, S. Histochem. Cell Biol. (2003) [Pubmed]
  18. Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase. Levy-Adam, F., Abboud-Jarrous, G., Guerrini, M., Beccati, D., Vlodavsky, I., Ilan, N. J. Biol. Chem. (2005) [Pubmed]
  19. Cellular differentiation, cytidine analogs and DNA methylation. Jones, P.A., Taylor, S.M. Cell (1980) [Pubmed]
  20. Methylation of mouse liver DNA studied by means of the restriction enzymes msp I and hpa II. Singer, J., Roberts-Ems, J., Riggs, A.D. Science (1979) [Pubmed]
  21. Degranulating mast cells secrete an endoglycosidase that degrades heparan sulfate in subendothelial extracellular matrix. Bashkin, P., Razin, E., Eldor, A., Vlodavsky, I. Blood (1990) [Pubmed]
  22. Macrophage and foam cell release of matrix-bound growth factors. Role of plasminogen activation. Falcone, D.J., McCaffrey, T.A., Haimovitz-Friedman, A., Vergilio, J.A., Nicholson, A.C. J. Biol. Chem. (1993) [Pubmed]
  23. Localization of Perlecan and Heparanase in Hertwig's Epithelial Root Sheath During Root Formation in Mouse Molars. Hirata, A., Nakamura, H. J. Histochem. Cytochem. (2006) [Pubmed]
  24. Cloning, expression, and purification of mouse heparanase. Miao, H.Q., Navarro, E., Patel, S., Sargent, D., Koo, H., Wan, H., Plata, A., Zhou, Q., Ludwig, D., Bohlen, P., Kussie, P. Protein Expr. Purif. (2002) [Pubmed]
  25. Mechanistic aspects of genome-wide demethylation in the preimplantation mouse embryo. Kafri, T., Gao, X., Razin, A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  26. Clonal inheritance of the pattern of DNA methylation in mouse cells. Stein, R., Gruenbaum, Y., Pollack, Y., Razin, A., Cedar, H. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  27. Methylation of satellite sequences in mouse spermatogenic and somatic DNAs. Ponzetto-Zimmerman, C., Wolgemuth, D.J. Nucleic Acids Res. (1984) [Pubmed]
  28. Heparanase expression at the invasion front of human head and neck cancers and correlation with poor prognosis. Beckhove, P., Helmke, B.M., Ziouta, Y., Bucur, M., Dörner, W., Mogler, C., Dyckhoff, G., Herold-Mende, C. Clin. Cancer Res. (2005) [Pubmed]
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