Tissue distribution of hepatopoietin-A: a heparin-binding polypeptide growth factor for hepatocytes.

Zarnegar, Reza; Muga, Stephanie J.; Rahija, Richard J.; Michalopoulos, George K.

doi:10.1073/pnas.87.3.1252

Cited by 125 publications

(62 citation statements)

References 25 publications

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“…These in vivo results extend previous in vitro findings suggesting that HGF is one of the most potent mitogens and insulinotropic agents for beta cells (14,19,20). Since HGF is produced in the pancreas (12)(13)(14)(15)(16)(17) and the c-Met receptor is localized in the islet beta cells (14), it seems likely that HGF may play a paracrine and/or autocrine physiological role in the growth and development of the pancreatic islet.…”

Section: Discussionsupporting

confidence: 77%

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Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Garcı́a-Ocaña¹,

Takane²,

Syed³

et al. 2000

Journal of Biological Chemistry

227

211

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Hepatocyte growth factor (HGF) is produced in pancreatic mesenchyme-derived cells and in islet cells. In vitro, HGF increases the insulin content and proliferation of islets. To study the role of HGF in the islet in vivo, we have developed three lines of transgenic mice overexpressing mHGF using the rat insulin II promoter (RIP). Each RIP-HGF transgenic line displays clear expression of HGF mRNA and protein in the islet. RIPmHGF mice are relatively hypoglycemic in post-prandial and fasting states compared with their normal littermates. They display inappropriate insulin production, striking overexpression of insulin mRNA in the islet, and a 2-fold increase in the insulin content in islet extracts. Importantly, beta cell replication rates in vivo are two to three times higher in RIP-HGF mice. This increase in proliferation results in a 2-3-fold increase in islet mass. Moreover, the islet number per pancreatic area was also increased by approximately 50%. Finally, RIP-mHGF mice show a dramatically attenuated response to the diabetogenic effects of streptozotocin. We conclude that the overexpression of HGF in the islet increases beta cell proliferation, islet number, beta cell mass, and total insulin production in vivo. These combined effects result in mild hypoglycemia and resistance to the diabetogenic effects of streptozotocin. Hepatocyte growth factor (HGF)1 is a mesenchyme-derived protein originally identified as a circulating factor implicated in liver regeneration after hepatic injury or hepatectomy (1-3). It is now recognized that HGF also exhibits its mitogenic, motogenic, and morphogenic activities in a wide variety of cells (4, 5). The active form of HGF is a disulfide-linked heterodimeric protein, which is composed of a 69-kDa ␣-chain and a 34-kDa ␤-chain, containing four kringle domains and a serine protease-like domain, respectively. Active HGF derives from an inactive single chain precursor that is processed and activated by proteolysis. Four proteases have been reported to date to activate HGF in vitro, including blood coagulation factor XIIa, urokinase, tissue-type plasminogen activator, and a serumderived serine protease named HGF activator (6 -9). HGF is primarily a paracrine factor produced by mesenchymal cells that acts on epithelial cells through a membrane-spanning tyrosine kinase receptor, the protein product of the proto-oncogene, c-met (5, 10, 11). The receptor, like the ligand, has a widespread distribution.Messenger RNAs encoding HGF and the HGF receptor, cmet, are highly expressed during the early development of the pancreas, and then maintained at a low level during puberty and adult life (12)(13)(14). HGF has been detected immunohistochemically in the exocrine portion of rabbit pancreas, and in rat and human pancreatic islet cells (15-17). Tissue-type plasminogen activator has been detected in the rat endocrine pancreas, preferentially in somatostatin cells (18). In addition, confocal immunofluorescent studies have preferentially colocalized the c-Met receptor protein to insulin-conta...

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Section: Discussionsupporting

confidence: 77%

“…HGF has been detected immunohistochemically in the exocrine portion of rabbit pancreas, and in rat and human pancreatic islet cells (15)(16)(17). Tissue-type plasminogen activator has been detected in the rat endocrine pancreas, preferentially in somatostatin cells (18).…”

mentioning

confidence: 99%

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Garcı́a-Ocaña¹,

Takane²,

Syed³

et al. 2000

Journal of Biological Chemistry

227

211

View full text Add to dashboard Cite

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“…The demonstration that HGF also had a strong effect in Eck's fistula model is the first evidence of its in vivo potency. HGF is produced in multiple sites, including the exocrine portion of the pancreas (46), and its physiological role remains to be determined. However, using in vitro testing for growth effects, researchers might pass over as unexciting not only insulin and IGF-II but also cyclosporine (47), FK 506 (47) and HSS.…”

Section: Discussionmentioning

confidence: 99%

Screening for candidate hepatic growth factors by selective portal infusion after canine Eck's fistula

Francavilla

1991

Hepatology

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“…Expressão elevada do met/receptor do HFG nas células foliculares neoplásicas parece dever-se a uma relação parácrina entre o fator estimulante e o receptor já que o HGF é secretado pelas células parafoliculares tireoidianas 25,26 .…”

Section: Receptores Tirosinoquinasesunclassified

A biologia molecular no prognóstico do carcinoma da tireóide

Rodrigues

2003

Rev. Col. Bras. Cir.

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INTRODUÇÃOO carcinoma da tireóide, como outros tumores malignos do organismo humano, origina-se de uma única célula, alterada por lesões dos genes que controlam a proliferação celular. O comportamento biológico do câncer tireoidiano é muito variado e embora, em sua maioria, apresente comprometimento clinicamente indolente, em alguns casos assume características agressivas, com invasão local e metástases à distância, que podem resultar no óbito do paciente.Excluindo-se os carcinomas anaplásicos, invariavelmente fatais com qualquer tipo de tratamento, os diferenciados e os medulares admitem terapêuticas mais ou menos agressivas, de acordo com o comportamento biológico do tumor. Por isso, nas duas últimas déca-das, diversos autores vêm procurando definir os fatores de risco que apresentam valor prognóstico na evolução destes tumores, especialmente na variedade diferenciada, tornando possível dividi-los em dois grupos: tumor de alto e de baixo risco, com condutas terapêuti-cas diferentes em cada grupo [1][2][3][4][5] . Os fatores de risco avaliados baseiam-se em dados clínicos e anatomopatológicos que em análises multivariadas, mostraram-se independentemente responsáveis pelo prognóstico da doença. Entretanto, mesmo em pacientes considerados de baixo risco nestas classificações, alguns tumores podem eventualmente desenvolver comportamento mais agressivo. O estudo da expressão de oncogenes, de antioncogenes bem como de genes implicados na adesão celular e na disseminação tumoral, tem procurado aprimorar a avaliação prognóstica dos tumores tireoidianos a nível molecular 6 . ONCOGENES E ANTIONCOGENES NO CÂNCER DE TIREÓIDEUm melhor conhecimento da biologia molecular possibilitou o entendimento de alterações celulares que levam à formação e disseminação dos tumores. Diversos fatores estimulam a proliferação e a diferenciação celulares (genes estimuladores); outros são inibidores desta proliferação (genes supressores). Do inter-relacionamento adequado destes fatores resulta o funcionamento normal de órgãos e tecidos. As proteínas normais codificadas pelos genes estimuladores atuam na membrana celular, no citoplasma e no núcleo. Agem como fatores de crescimento, como receptores destes fatores, como proteínas envolvidas na transmissão de sinais dentro das células (mensageiros secundários) e como proteínas reguladoras nucleares. Na tireóide, os principais fatores estimulantes da proliferação celular e/ou de suas funções são o hormônio tireotrófico da hipófise (TSH), o fator de crescimento epidérmico (EGF), o fator de crescimento transformador ∝ (TGF∝) e o fator de crescimento semelhantes à insulina (IGF). Outros fatores menos importantes mas com ação semelhante, são o fator de crescimento fibroblasto básico (BFGF), a gonadotropina coriônica humana (hCG), o hormônio de crescimento (GH) e o fator de crescimento do hepatócito (HGF) entre outros. Entre os genes supressores estão o p53 e o fator de crescimento transformador β (TGFβ).Os fatores estimulantes codificam receptores específicos na célula que, ativados, modificam e t...

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Tissue distribution of hepatopoietin-A: a heparin-binding polypeptide growth factor for hepatocytes.

Cited by 125 publications

References 25 publications

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Screening for candidate hepatic growth factors by selective portal infusion after canine Eck's fistula

A biologia molecular no prognóstico do carcinoma da tireóide

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