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Gene Review

HAS1  -  hyaluronan synthase 1

Homo sapiens

Synonyms: HA synthase 1, HAS, HuHAS1, Hyaluronan synthase 1, Hyaluronate synthase 1, ...
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Disease relevance of HAS1

  • Our data suggests that HAS1 might be a useful positive marker of malignant mesothelioma [1].
  • The expression level of HAS1 was significantly higher in mesotheliomas than in pulmonary adenocarcinoma (P=0.0036) [1].
  • Tissues obtained from 59 endometrial cancer patients were immunostained by the avidin-biotin-peroxidase complex method using anti-HAS1, anti-HAS2, anti-HAS3 and anti-CD44 antibody [2].
  • In the 33 ovarian cancer cases, 12 cases had positive expression of HAS1, 21 cases had positive expression of HAS2 and 11 cases had positive expression of HAS3 [3].
  • These results suggest that HAS1 expression in ovarian cancer may be associated with disease progression through angiogenesis and is an independent predictor of patient survival [3].

High impact information on HAS1


Chemical compound and disease context of HAS1


Biological context of HAS1


Anatomical context of HAS1

  • HAS2 mRNA was usually predominant in chondrocytes, whereas synovial cells contained increased amounts of HAS1 [15].
  • HAS usage in uncultured cartilage and synovial tissues was similar to that in the cultured cells, with HAS2 message being the predominant species in cartilage and HAS1 usually being the predominant species in synovium [15].
  • Expression of the mouse Has3 open reading frame in transfected COS-1 cells led to high levels of hyaluronan synthesis, as determined through a classical particle exclusion assay, and by in vitro HA synthase assays [16].
  • All three genes encode predicted plasma membrane proteins with multiple transmembrane domains and approximately 25% amino acid sequence identity to the Streptococcus pyogenes HA synthase, HasA [13].
  • Furthermore, we suggest that overexpression of HAS1 and its variants in combination with HAS3 may form an HA matrix around WM cells, thus preventing their elimination by the immune system, and it promotes their migration and may facilitate the spread of disease [17].

Associations of HAS1 with chemical compounds

  • Additional experiments revealed that in FLS, leflunomide specifically blocked the induction of HAS1 [18].
  • These findings also support the concept that IL-1beta-induced HAS1 activation depends on the activation of tyrosine kinases, and indicate that leflunomide blocks HA release by suppressing tyrosine kinases rather than through inhibition of NF-kappaB translocation [18].
  • Furthermore, reconstituting the pyrimidine synthase pathway did not lead to the restoration of IL-1beta-induced HAS1 activation [18].
  • Glucocorticoids inhibit induced and non-induced mRNA accumulation of genes encoding hyaluronan synthases (HAS): hydrocortisone inhibits HAS1 activation by blocking the p38 mitogen-activated protein kinase signalling pathway [19].
  • HAS2, HAS1, and HA synthesis were strongly induced by vasodilatory prostaglandins via Gs-coupled prostaglandin receptors [20].

Regulatory relationships of HAS1


Other interactions of HAS1

  • More importantly, two tyrosine kinase inhibitors mimicked the effect of leflunomide in that both blocked IL-1beta-induced HAS1 activation without affecting HAS2 or HAS3 [18].
  • In contrast to the activatory effect on HAS1, TGF-beta dose-dependently suppresses HAS3 mRNA [11].
  • Our experiments, testing a series of stimuli including tumor necrosis factor alpha (TNFalpha), demonstrate that TGF-beta is the most potent stimulus for HAS1 transcription [11].
  • These data point at HAS1 activation as the possible cause for unfettered HA production in rheumatoid arthritis and might explain, at least in part, the beneficial effects of leflunomide treatment [18].
  • When the ratio of tumor to normal tissue in the HAS1 level was compared with that of the HA receptor transcript level, there was a positive correlation with that of the CD44 variant 6 level at Dukes' stage C [23].

Analytical, diagnostic and therapeutic context of HAS1

  • The expression of HAS1 mRNA was not significantly affected by either cytokine, and HAS2 mRNA expression was undetectable under either basal or cytokine-stimulated conditions by northern blot using total RNA [24].
  • In the 23 patients that received chemotherapy, the expression of HAS1, HAS2 and HAS3 was unrelated to the chemotherapy response [3].
  • Molecular cloning and characterization of a cDNA encoding the third putative mammalian hyaluronan synthase [16].
  • In contrast, HAS1 mRNA was detected by Northern blot analysis in only one of the strains treated with IL-1beta, but in three of five strains examined by RT-PCR [25].
  • HA histochemistry utilized a biotinylated HA binding peptide (n = 15), while HA synthase (HAS) immunohistochemistry utilized an antibody recognizing HAS1, HAS2 HAS3 (n = 24) [26].


  1. Hyaluronan synthase expression in pleural malignant mesotheliomas. Kanomata, N., Yokose, T., Kamijo, T., Yonou, H., Hasebe, T., Itano, N., Kimata, K., Ochiai, A. Virchows Arch. (2005) [Pubmed]
  2. Role of hyaluronan and hyaluronan synthase in endometrial cancer. Yabushita, H., Kishida, T., Fusano, K., Kanyama, K., Zhuo, L., Itano, N., Kimata, K., Noguchi, M. Oncol. Rep. (2005) [Pubmed]
  3. Hyaluronan synthase expression in ovarian cancer. Yabushita, H., Noguchi, M., Kishida, T., Fusano, K., Noguchi, Y., Itano, N., Kimata, K., Noguchi, M. Oncol. Rep. (2004) [Pubmed]
  4. Intronic splicing of hyaluronan synthase 1 (HAS1): a biologically relevant indicator of poor outcome in multiple myeloma. Adamia, S., Reiman, T., Crainie, M., Mant, M.J., Belch, A.R., Pilarski, L.M. Blood (2005) [Pubmed]
  5. Characterization of hyaluronan synthase expression and hyaluronan synthesis in bone marrow mesenchymal progenitor cells: predominant expression of HAS1 mRNA and up-regulated hyaluronan synthesis in bone marrow cells derived from multiple myeloma patients. Calabro, A., Oken, M.M., Hascall, V.C., Masellis, A.M. Blood (2002) [Pubmed]
  6. Rapid chemoenzymatic synthesis of monodisperse hyaluronan oligosaccharides with immobilized enzyme reactors. DeAngelis, P.L., Oatman, L.C., Gay, D.F. J. Biol. Chem. (2003) [Pubmed]
  7. Inhibition of hyaluronate synthesis. Prehm, P. Biochem. J. (1985) [Pubmed]
  8. Uronate peaks and urinary hyaluronic acid levels correlate with interstitial cystitis severity. Lokeshwar, V.B., Selzer, M.G., Unwala, D.J., Estrella, V., Gomez, M.F., Golshani, R., Kester, R.R., Klumpp, D.J., Gousse, A.E. J. Urol. (2006) [Pubmed]
  9. Study of hyaluronan synthase inhibitor, 4-methylumbelliferone derivatives on human pancreatic cancer cell (KP1-NL). Morohashi, H., Kon, A., Nakai, M., Yamaguchi, M., Kakizaki, I., Yoshihara, S., Sasaki, M., Takagaki, K. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  10. 4-methylumbelliferone, a hyaluronan synthase suppressor, enhances the anticancer activity of gemcitabine in human pancreatic cancer cells. Nakazawa, H., Yoshihara, S., Kudo, D., Morohashi, H., Kakizaki, I., Kon, A., Takagaki, K., Sasaki, M. Cancer Chemother. Pharmacol. (2006) [Pubmed]
  11. Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. Stuhlmeier, K.M., Pollaschek, C. J. Biol. Chem. (2004) [Pubmed]
  12. Differential regulation by IL-1beta and EGF of expression of three different hyaluronan synthases in oral mucosal epithelial cells and fibroblasts and dermal fibroblasts: quantitative analysis using real-time RT-PCR. Yamada, Y., Itano, N., Hata, K., Ueda, M., Kimata, K. J. Invest. Dermatol. (2004) [Pubmed]
  13. Chromosomal localization of the human and mouse hyaluronan synthase genes. Spicer, A.P., Seldin, M.F., Olsen, A.S., Brown, N., Wells, D.E., Doggett, N.A., Itano, N., Kimata, K., Inazawa, J., McDonald, J.A. Genomics (1997) [Pubmed]
  14. The human hyaluronan synthase genes: genomic structures, proximal promoters and polymorphic microsatellite markers. Monslow, J., Williams, J.D., Norton, N., Guy, C.A., Price, I.K., Coleman, S.L., Williams, N.M., Buckland, P.R., Spicer, A.P., Topley, N., Davies, M., Bowen, T. Int. J. Biochem. Cell Biol. (2003) [Pubmed]
  15. Differential regulation and expression of hyaluronan synthases in human articular chondrocytes, synovial cells and osteosarcoma cells. Recklies, A.D., White, C., Melching, L., Roughley, P.J. Biochem. J. (2001) [Pubmed]
  16. Molecular cloning and characterization of a cDNA encoding the third putative mammalian hyaluronan synthase. Spicer, A.P., Olson, J.S., McDonald, J.A. J. Biol. Chem. (1997) [Pubmed]
  17. Abnormal expression of hyaluronan synthases in patients with Waldenstrom's macroglobulimenia. Adamia, S., Crainie, M., Kriangkum, J., Mant, M.J., Belch, A.R., Pilarski, L.M. Semin. Oncol. (2003) [Pubmed]
  18. Effects of leflunomide on hyaluronan synthases (HAS): NF-kappa B-independent suppression of IL-1-induced HAS1 transcription by leflunomide. Stuhlmeier, K.M. J. Immunol. (2005) [Pubmed]
  19. Glucocorticoids inhibit induced and non-induced mRNA accumulation of genes encoding hyaluronan synthases (HAS): hydrocortisone inhibits HAS1 activation by blocking the p38 mitogen-activated protein kinase signalling pathway. Stuhlmeier, K.M., Pollaschek, C. Rheumatology (Oxford, England) (2004) [Pubmed]
  20. Differential regulation of hyaluronic acid synthase isoforms in human saphenous vein smooth muscle cells: possible implications for vein graft stenosis. van den Boom, M., Sarbia, M., von Wnuck Lipinski, K., Mann, P., Meyer-Kirchrath, J., Rauch, B.H., Grabitz, K., Levkau, B., Schrör, K., Fischer, J.W. Circ. Res. (2006) [Pubmed]
  21. Prostaglandin E(2): A potent activator of hyaluronan synthase 1 in type-B-synoviocytes. Stuhlmeier, K.M. Biochim. Biophys. Acta (2007) [Pubmed]
  22. Activation of adenosine receptor on gingival fibroblasts. Hashikawa, T., Takedachi, M., Terakura, M., Yamada, S., Thompson, L.F., Shimabukuro, Y., Murakami, S. J. Dent. Res. (2006) [Pubmed]
  23. Elevated transcript level of hyaluronan synthase1 gene correlates with poor prognosis of human colon cancer. Yamada, Y., Itano, N., Narimatsu, H., Kudo, T., Morozumi, K., Hirohashi, S., Ochiai, A., Ueda, M., Kimata, K. Clin. Exp. Metastasis (2004) [Pubmed]
  24. Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes. Sayo, T., Sugiyama, Y., Takahashi, Y., Ozawa, N., Sakai, S., Ishikawa, O., Tamura, M., Inoue, S. J. Invest. Dermatol. (2002) [Pubmed]
  25. Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1beta in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy. Kaback, L.A., Smith, T.J. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  26. Expression patterns of hyaluronan, hyaluronan synthases and hyaluronidases indicate a role for hyaluronan in the progression of endometrial cancer. Paiva, P., Van Damme, M.P., Tellbach, M., Jones, R.L., Jobling, T., Salamonsen, L.A. Gynecol. Oncol. (2005) [Pubmed]
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