Polypeptide of human-origin hyaluronate synthetase and DNA encod

Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives

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435 6, 435 691, 435183, 536 231, C12N 926, C12N 900

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active

061629081

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a polypeptide of a hyaluronan synthase of human origin and a DNA encoding the same.


BACKGROUND ART

Hyaluronan is one of high molecular weight glycosaminoglycans and is constituted by repeated .beta.-1,4 linked disaccharide units, each of the unit being composed of glucuronic acid linked to N-acetylglucosamine by a .beta.-1,3 bond (GlcUA.beta.1-3GlcNAc; GlcUA and GlcNAc represent glucuronic acid and N-acetylglucosamine, respectively). Hyaluronan is a characteristic constituent of the extracellular matrix at the early stage of morphogenesis of animals. Its synthesis is regulated spatially and temporally (Toole, B. P. (1981) Cell Biology of the Extracellular Matrix (Hey, E. D., ed.) pp. 259-294, Plenum, New York). Accumulation of hyaluronan on the cell surface is correlated with regulation of behavior of cells, particularly migration, adhesion, cure of wounds, infiltration of tumors, and the like (Turley, E. A. (1989) The Biology of Hyaluronan, Ciba Foundation Symposium 143, pp. 121-137; Wiley, Chichester, England; Knudson, W., Biswas, C., Li, X.-Q., Nemec, R. E., and Tool, B. P. (1989) The Biology of Hyaluronan, Ciba Foundation Symposium 143, pp. 150-169, Wiley, Chichester, England; Laurent, T. C., and Fraser, J. R. E. (1992) FASEB J. 6, 2397-2404; Kimata, K., Honma, Y., Okayama, M., Oguri, K., Hozumi, M., and Suzuki, S. (1983) Cancer Res. 43, 1347-1354).
Biosysthesis of hyaluronan has been widely studied using a procaryote, Streptococci. A recent report revealed that a structural gene of hyaluronan synthase derived from Streptococcus pyogenes which is a procaryote was isolated (DeAngelis, P. L., Papaconstantinou, J., and Weigel, P. H. (1993) J. Biol. Chem. 268, 19181-19184). In contrast, little is known about the biosynthesis mechanism of hyaluronan in eucaryotes. Attempts have been made to purify eucaryotic hyaluronan synthase. However, some reports showed that the obtained enzyme lost its activity (Mian, N. (1986) Biochem. J. 237, 343-357; Ng, K. F., and Schwartz, N. B. (1989) J. Biol. Chem. 264, 11776-11783; Klewes, L., Turley, E. A., and Prehm, P. (1993) Biochem. J. 290, 791-795). Any DNA encoding a polypeptide of eucaryotic hyaluronan synthase is not known.
If a polypeptide of hyaluronan synthase derived from eucaryotes, particularly human, and a DNA encoding it are obtained, they would be useful for treatments, including gene therapy, of diseases caused by decreased expression of hyaluronan in humans. In addition, these substances would also be useful for gene therapy for suppressing metastasis of cancer using an antisense DNA, RNA, or the like as well as development of hyaluronan synthase-specific inhibitors.


DISCLOSURE OF THE INVENTION

The object of the present invention is to provide a polypeptide of a hyaluronan synthase of human origin and a DNA encoding the polypeptide.
The present inventors intensively investigated to achieve the above object and, as a result, succeeded in cloning a cDNA encoding a polypeptide of hyaluronan synthase, which has hyaluronan synthase activity, from cells of an organism except human and, by using a fragment derived from the cDNA, cloning a cDNA encoding a polypeptide of a hyaluronan synthase of human origin. Thus, the present invention was completed.
The present invention provides a DNA encoding the following polypeptide (a) or (b):
Further, the present invention also provides a DNA encoding any one of the following polypeptides (a) to (c): which has a substitution, deletion or insertion of one or more amino acid residues that does not substantially lower an activity of synthesizing hyaluronan; and
The above-described DNA preferably encodes the whole or the amino acid sequence shown by SEQ ID NO: 4. It also preferably has at least a part of the nucleotide sequence shown by SEQ ID NO: 1, more preferably has a nucleotide sequence of from position 149 to position 1777 of the nucleotide sequence shown by SEQ ID NO: 1. In the present invention, the DNA of the present invention includes a DNA or an RNA complementary

REFERENCES:
Gibco BRL/Life Technologies Catalogue 1993-1994, p. 7--7, 1993.
Andrew P. Spicer, et al., Molecular Cloning and Characterization of a Putative Mouse Hyaluronan Synthase, The Journal of biological Chemistry vol. 217, No. 38, pp. 23400-23406, Sep. 20, 1996.
Andrew P. Spicer, et al., Molecular cloning and Characterization of a cDNA Encoding the Third Putative Mammalian Hyaluronan Synthase, The Journal of Biological Chemistry, vol. 272, No. 14, pp. 8957-8961, Apr. 4, 1997.
Naoki Itano, et al., Expression Cloning and Molecular Characterization of HAS Protein, a Eukaryotic Hyaluronan Synthase, The Journal of Biological Chemistry vol., 271, No. 17, pp. 9875-9879, Apr. 26, 1998.
Naoki Itano, et al., Molecular Cloning of Human Hyaluronan Synthase, Biochemical and Biophysical Research Communications, vol. 222, No, 3, pp. 816-821, May 24, 1996.
Ann M. Shyjan, et al., Functional Cloning of the CDNA for a Human Hyaluronan synthase, The Journal of Biological Chemistry Vo. 271, No. 38, pp. 23395-23399, Sep. 20, 1996.

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