Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1995-09-22
1998-09-15
Ulm, John
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435243, 4353201, 435325, 530399, 530413, 536 2351, C07K 132, C07K 14475, C12N 510, C12N 1518
Patent
active
058077111
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a parenchymal hepatocyte growth substance originating in a human or animal liver and having an activity of effecting the extracellular growth of parenchymal hepatocytes, and a gene coding for the above substance.
More particularly, the present invention relates to a parenchymal hepatocyte growth substance originating in a human or animal liver which is expected to be effective for the treatment of liver diseases through the improvement of liver functions by proliferating normal hepatocytes in many liver diseases including hepatitis, liver cirrhosis and hepatoma, as well as a gene coding for the said substance.
BACKGROUND ART
It has been reported from old that when the liver suffers from various damages, regeneration of the liver occurs. The first report that partial hepatectomy of rat liver caused liver regeneration was made by Higgins, G. M., et al. in Arch. Pathol., 12, 186-202 (1931).
A hepatocyte growth factor (HGF) from rat platelets was found as a substance for promoting the growth of liver cells by Toshikazu Nakamura et al., see Biochem. Biophys. Res. Commun., 122, 1450-1459 (1984).
Likewise human HGF (hHGF) originating in human blood was discovered by Aida et al., see Japanese Patent Application KOKAI No. 63-22526.
However, recent studies reveal that these substances (factors) are one of cytokines produced in many organs (lung, liver, kidney, spleen, etc.) of rat and human and also exhibit the activities of accelerating infiltration of human cancer cells (renal tubule MDCK, lung cancer cells 549) and stimulating the growth of other normal cells (epithelial cells, renal tubular cells, keratinocytes, melanocytes), see Nippon Rinsho, 50, 1918 (1992).
A substance having diverse activities is anticipated to cause side effects in vivo and hence, it is desired to develop a substance capable of specifically stimulating the growth of hepatocytes.
In general, most of such substances (factors) are proteinaceous factors produced in a trace amount in vivo. In order to utilize such substances as reagents for studies, agents for diagnosis and therapeutic agents, it is thus required to produce these substances in a large scale and also for this reason, it is desired to clarify the structure of such substances.
DISCLOSURE OF INVENTION
The present inventors have made extensive studies with an attempt to obtain a novel gene coding for a hepatocyte growth factor from a rat liver and have succeeded in acquiring the novel gene coding for a hepatocyte growth factor from the rat residual liver after partial hepatectomy. Expression of this gene has resulted in successfully obtaining a novel parenchymal hepatocyte growth substance and successfully isolating and purifying the same substance from the rat residual liver after partial hepatectomy. Furthermore, the same gene has been successfully acquired from human liver. The present invention has thus been accomplished. That is, as a first aspect the present invention relates to: substance originating in a human or animal liver and having the following physico-chemical properties and physiological activities: about 63,000 to about 69,000, an estimated molecular weight according to reductive SDS-PAGE of about 32,000 to about 36,000 and an estimated molecular weight according to gel filtration of about 60 to about 70 Kd; lost by a heat treatment at 95.degree. C. for 5 minutes, a treatment with trypsin or a treatment with chymotrypsin;
As a second aspect, the present invention relates to a gene coding for the parenchymal hepatocyte growth substance described above.
As a third aspect, the present invention relates to a process for producing a parenchymal hepatocyte growth substance which comprises transforming a host cell with an expression vector bearing the gene coding for the said parenchymal hepatocyte growth substance, culturing the resulting transformant and collecting the hepatic parenchymal cell growth substance from the culture medium.
As a fourth aspect, the present invention relates to as process for producing the
REFERENCES:
patent: 4960700 (1990-10-01), Malfroy-Camine et al.
patent: 5155218 (1992-10-01), Weinshank et al.
Database WPI, Section Ch, Week 9201, Derwent Publications Ltd., Class B04, AN 92-002670, "Recombinant Rat Liver Parenchymatous Cell Growth Factor Providing Means for Growth of Liver Parenchymatous Cell Outside of Living Body", JP 03 255 096 A (Toyobo KK), 13 Nov. 1991.
Yamamoto et al. Biochem. Biophys. Res. Comm. 193(2): 681-687, 1993.
Hanada Kazunori
Hara Hiroshi
Matsuki Yumiko
Shindo Saeko
Yoshimura Hiromitsu
Saoud Christine
Taisho Pharmaceutical Co. Ltd.
Ulm John
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