Activation of Wnt/β‐catenin pathway during hepatocyte growth factor–induced hepatomegaly in mice

Hepatocyte growth factor (HGF) and β‐catenin both play a crucial role in stimulating hepatocyte proliferation, but whether these 2 pathways cooperate in inducing hepatocyte proliferation is unclear. We have previously reported that β‐catenin forms a complex with c‐Met (HGF receptor) that undergoes d...

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Veröffentlicht in:Hepatology (Baltimore, Md.) Md.), 2006-10, Vol.44 (4), p.992-1002
Hauptverfasser: Apte, Udayan, Zeng, Gang, Muller, Peggy, Tan, Xinping, Micsenyi, Amanda, Cieply, Benjamin, Dai, Chunsun, Liu, Youhua, Kaestner, Klaus H., Monga, Satdarshan P. S.
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container_end_page 1002
container_issue 4
container_start_page 992
container_title Hepatology (Baltimore, Md.)
container_volume 44
creator Apte, Udayan
Zeng, Gang
Muller, Peggy
Tan, Xinping
Micsenyi, Amanda
Cieply, Benjamin
Dai, Chunsun
Liu, Youhua
Kaestner, Klaus H.
Monga, Satdarshan P. S.
description Hepatocyte growth factor (HGF) and β‐catenin both play a crucial role in stimulating hepatocyte proliferation, but whether these 2 pathways cooperate in inducing hepatocyte proliferation is unclear. We have previously reported that β‐catenin forms a complex with c‐Met (HGF receptor) that undergoes dissociation because of β‐catenin tyrosine phosphorylation on stimulation by HGF. It is also known that delivery of the human HGF gene cloned in a plasmid under a CMV promoter results in hepatomegaly in mice. In addition, recently characterized β‐catenin transgenic mice also showed hepatomegaly. The present study was based on the hypothesis that HGF‐induced hepatomegaly is mediated, at least in part, by activation of the Wnt/β‐catenin pathway. Here we report that delivery of the human HGF gene delivery in mice led to hepatomegaly via β‐catenin activation in the liver in 1‐ and 4‐week studies. The mechanisms of β‐catenin activation in the 1‐week study included loss of c‐Met–β‐catenin association as well as canonical β‐catenin activation, leading to its nuclear translocation. In the 4‐week study, β‐catenin activation was observed via canonical mechanisms, whereas the c‐Met–β‐catenin complex remained unchanged. In both studies there was an associated increase in the E‐cadherin–β‐catenin association at the membrane. In addition, we generated liver‐specific β‐catenin knockout mice, which demonstrated significantly smaller livers. HGF gene delivery failed to induce hepatomegaly in these β‐catenin conditionally null mice. In conclusion, β‐catenin‐ and HGF‐mediated signaling pathways cooperate in hepatocyte proliferation, which may be crucial in liver development, regeneration following partial hepatectomy, and pathogenesis of hepatocellular carcinoma. (HEPATOLOGY 2006;44:992–1002.)
doi_str_mv 10.1002/hep.21317
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Here we report that delivery of the human HGF gene delivery in mice led to hepatomegaly via β‐catenin activation in the liver in 1‐ and 4‐week studies. The mechanisms of β‐catenin activation in the 1‐week study included loss of c‐Met–β‐catenin association as well as canonical β‐catenin activation, leading to its nuclear translocation. In the 4‐week study, β‐catenin activation was observed via canonical mechanisms, whereas the c‐Met–β‐catenin complex remained unchanged. In both studies there was an associated increase in the E‐cadherin–β‐catenin association at the membrane. In addition, we generated liver‐specific β‐catenin knockout mice, which demonstrated significantly smaller livers. HGF gene delivery failed to induce hepatomegaly in these β‐catenin conditionally null mice. 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S.</creatorcontrib><title>Activation of Wnt/β‐catenin pathway during hepatocyte growth factor–induced hepatomegaly in mice</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Hepatocyte growth factor (HGF) and β‐catenin both play a crucial role in stimulating hepatocyte proliferation, but whether these 2 pathways cooperate in inducing hepatocyte proliferation is unclear. We have previously reported that β‐catenin forms a complex with c‐Met (HGF receptor) that undergoes dissociation because of β‐catenin tyrosine phosphorylation on stimulation by HGF. It is also known that delivery of the human HGF gene cloned in a plasmid under a CMV promoter results in hepatomegaly in mice. In addition, recently characterized β‐catenin transgenic mice also showed hepatomegaly. The present study was based on the hypothesis that HGF‐induced hepatomegaly is mediated, at least in part, by activation of the Wnt/β‐catenin pathway. Here we report that delivery of the human HGF gene delivery in mice led to hepatomegaly via β‐catenin activation in the liver in 1‐ and 4‐week studies. The mechanisms of β‐catenin activation in the 1‐week study included loss of c‐Met–β‐catenin association as well as canonical β‐catenin activation, leading to its nuclear translocation. In the 4‐week study, β‐catenin activation was observed via canonical mechanisms, whereas the c‐Met–β‐catenin complex remained unchanged. In both studies there was an associated increase in the E‐cadherin–β‐catenin association at the membrane. In addition, we generated liver‐specific β‐catenin knockout mice, which demonstrated significantly smaller livers. HGF gene delivery failed to induce hepatomegaly in these β‐catenin conditionally null mice. 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Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Mice, Knockout</subject><subject>Other diseases. 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S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of Wnt/β‐catenin pathway during hepatocyte growth factor–induced hepatomegaly in mice</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2006-10</date><risdate>2006</risdate><volume>44</volume><issue>4</issue><spage>992</spage><epage>1002</epage><pages>992-1002</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><abstract>Hepatocyte growth factor (HGF) and β‐catenin both play a crucial role in stimulating hepatocyte proliferation, but whether these 2 pathways cooperate in inducing hepatocyte proliferation is unclear. We have previously reported that β‐catenin forms a complex with c‐Met (HGF receptor) that undergoes dissociation because of β‐catenin tyrosine phosphorylation on stimulation by HGF. It is also known that delivery of the human HGF gene cloned in a plasmid under a CMV promoter results in hepatomegaly in mice. 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HGF gene delivery failed to induce hepatomegaly in these β‐catenin conditionally null mice. In conclusion, β‐catenin‐ and HGF‐mediated signaling pathways cooperate in hepatocyte proliferation, which may be crucial in liver development, regeneration following partial hepatectomy, and pathogenesis of hepatocellular carcinoma. (HEPATOLOGY 2006;44:992–1002.)</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>17006939</pmid><doi>10.1002/hep.21317</doi><tpages>11</tpages></addata></record>
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subjects Animals
beta Catenin - genetics
beta Catenin - metabolism
Biological and medical sciences
Cadherins - metabolism
Gastroenterology. Liver. Pancreas. Abdomen
Gene Transfer Techniques
Hepatocyte Growth Factor - genetics
Hepatocyte Growth Factor - metabolism
Hepatocyte Growth Factor - pharmacology
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatomegaly - chemically induced
Hepatomegaly - pathology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Mice
Mice, Inbred Strains
Mice, Knockout
Other diseases. Semiology
Plasmids
Promoter Regions, Genetic
Protein Transport
Signal Transduction
Wnt Proteins - metabolism
title Activation of Wnt/β‐catenin pathway during hepatocyte growth factor–induced hepatomegaly in mice
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