Hepatocyte growth factor is a potent mitogen for cultured rabbit renal tubular epithelial cells

Igawa, Tsukasa; Kanda, Shigeru; Kanetake, Hiroshi; Saitoh, Yutaka; Ichihara, Akira; Tomita, Yumiko; Nakamura, Toshikazu

doi:10.1016/0006-291x(91)91493-v

Cited by 245 publications

(103 citation statements)

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“…The ligand for the receptor encoded by c-met, HGF, is produced by mesenchymal cells from various organs (Stoker et al, 1987;Rubin et al, 1991;Sonnenberg et al, 1993) and has been shown to be a potent mitogen for a variety of epithelial cells in vitro, including hepatocytes (Strain et al, 1991), renal tubular cells (Igawa et al, 1991), melanocytes (Matsumoto et al, 1991a), keratinocytes (Matsumoto et al, 1991b), normal and oncogene-transformed thyroid cells (Eccles et al, 1996). Overexpression of the c-met protein by human epithelium may therefore confer increased sensitivity to HGF produced by surrounding stromal cells, thereby representing a signi®cant paracrine contribution to tumour growth.…”

Section: Introductionmentioning

confidence: 99%

Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells

et al. 1997

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Hepatocyte Growth Factor (HGF) receptor, encoded by the protooncogene c-met, is overexpressed in many human tumours, including those of thyroid epithelium. The absence in most cases of any primary structural abnormality of the met gene suggests that overexpression is secondary to mutation of other gene(s). To test this hypothesis we investigated the e ect on met expression of two activated oncogenes known to play a major role in thyroid oncogenesis, ras and ret. To minimize the possibility of unknown co-operating events, we introduced these genes directly into normal human thyrocytes in primary culture using amphotropic retroviral vectors and assessed met expression as early as possible in the resulting epithelial colonies. Double immuno¯uorescence revealed expression of met protein, strictly localized to cells expressing the mutant ras and ret vectors, expression in background normal cells being barely detectable. In contrast, colonies induced to proliferate at a comparable rate by a vector expressing SV40 T showed no increase in met expression. To permit quantitation by Western blotting we also extended these ®ndings to a thyroid cell line (R18) containing a zincinducible mutant ras gene. Induction of the oncogene led to a fourfold increase in met protein expression. We conclude that overexpression of met is induced by activation of the ras or ret signalling pathway and not simply by deregulation of the cell cycle per se. The data suggest that the proliferative advantage conferred by these oncogenes may be in part due to the resulting sensitization of tumour epithelium to paracrine HGF secreted by stromal cells.

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Section: Introductionmentioning

confidence: 99%

Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells

et al. 1997

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“…In response to tissue damage such as hepatic and renal injury, the inactive single chain form is converted to an active heterodimeric molecule exclusively in the injured tissue by limited proteolysis at a single site (1). The proteolytically activated HGF may be involved in regeneration of the injured tissue, because HGF is a potent mitogen for a variety of cells such as hepatocytes and renal tubular epithelial cells (3)(4)(5). Thus, the biological effects of HGF in the injured tissues are regulated through proteolytic processing.…”

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confidence: 99%

Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor

Shimomura

Denda

Kitamura

et al. 1997

Journal of Biological Chemistry

250

264

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Hepatocyte growth factor (HGF) activator is a serine protease that is produced and secreted by the liver and circulates in the blood as an inactive zymogen. In response to tissue injury, the HGF activator zymogen is converted to the active form by limited proteolysis. The activated HGF activator converts an inactive single chain precursor of HGF to a biologically active heterodimer in injured tissue. The activated HGF may be involved in the regeneration of the injured tissue. In this study, we purified an inhibitor of HGF activator from the conditioned medium of a human MKN45 stomach carcinoma cell line and molecularly cloned its cDNA. The sequence of the cDNA revealed that the inhibitor has two well defined Kunitz domains, suggesting that the inhibitor is a member of the Kunitz family of serine protease inhibitors. The sequence also showed that the primary translation product of the inhibitor has a hydrophobic sequence at the COOH-terminal region. Inhibitory activity toward HGF activator was detected in the membrane fraction as well as in the conditioned medium of MKN45 cells. These results suggest that the inhibitor may be produced as a membrane-associated form and secreted by the producing cells as a proteolytically truncated form.

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“…Molecular cloning of HGF cDNA revealed that both chains of HGF are encoded in a single gene (Miyazawa et al, 1989;Nakamura et al, 1989;Seki et al, 1990;Tashiro et al, 1990). Accumulating evidence indicates that, in addition to its effect on hepatocytes, HGF is a unique multifunctional cytokine acting on a wide variety of cells as a mitogen (Igawa et al, 1991;Kan et al, 1991;Rubin et al, 1991), a motogen (Gherardi et al, 1989;Gherardi and Stoker, 1991), a morphogen (Montesano et al, 1991), an angiogenetic factor (Bussolino et al, 1992;Grant et al, 1993) and a tumour cytotoxic factor (Higashio et al, 1990);Tajima et al, 1991). Indeed, HGF mRNA is expressed in various tissues, including kidney Nagaike et al, 1991), heart , lung Yanagita et al, 1992Yanagita et al, , 1993) and brain , as well as in injured liver (Kinoshita et al, 1989).…”

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confidence: 99%

Hepatocyte growth factor levels in bone marrow plasma of patients with leukaemia and its gene expression in leukaemic blast cells

Hino

Inaba²,

Goto³

et al. 1996

Br J Cancer

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Summary Hepatocyte growth factor (HGF) has been known as a multiple function factor, which also stimulates early haematopoiesis. In this study, we found that HGF was expressed at both the RNA and protein levels in acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML). In patients with AML (n = 20) and CML (n = 5), bone marrow plasma HGF concentrations were 20.44 ± 6.26 (mean ± s.e.) ng ml' and 7.17 ± 0.53 ng ml-' respectively. These were significantly higher (P< 0.01) than the value for normal subjects (n = 26): mean 0.92 ± 0.09 ng ml-'. Constitutive HGF production was observed in freshly prepared leukaemic blast cells from three patients with high HGF levels of bone marrow plasma. Expression of HGF mRNA was correlated with bone marrow plasma HGF levels. After complete remission was obtained in six patients, bone marrow plasma HGF levels were significantly decreased. In contrast, the HGF mRNA was less abundantly expressed in acute lymphoid leukaemia (ALL). In patients with ALL (n = 5), bone marrow plasma HGF concentration (0.69 ± 0.14 ng ml -) remained low within the value for normal subjects. These results suggest that some populations of myeloid lineage cells have the ability to produce HGF.

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Hepatocyte growth factor is a potent mitogen for cultured rabbit renal tubular epithelial cells

Cited by 245 publications

References 16 publications

Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells

Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells

Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor

Hepatocyte growth factor levels in bone marrow plasma of patients with leukaemia and its gene expression in leukaemic blast cells

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