HEPATOCYTE GROWTH-FACTOR IN TRANSGENIC MICE - EFFECTS ON HEPATOCYTE GROWTH, LIVER-REGENERATION AND GENE-EXPRESSION
HEPATOCYTE GROWTH-FACTOR IN TRANSGENIC MICE - EFFECTS ON HEPATOCYTE GROWTH, LIVER-REGENERATION AND GENE-EXPRESSION
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DOI：
10.1002/hep.1840190423
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发表时间：
1994-04-01
期刊：
影响因子：
13.5
通讯作者：
SCHMIDT, EV
中科院分区：
文献类型：
--
作者：
SHIOTA, G;WANG, TC;SCHMIDT, EV
肝细胞生长因子是体外肝细胞最有效的促有丝分裂原，近年来肝细胞生长因子作为肝再生的主要候选因子受到关注。然而，肝细胞生长因子在体外也表现出不同的活性，作为分散因子，作为上皮形态发生剂，作为多能有丝分裂原和作为生长抑制剂。因此，我们开发了在白蛋白调控序列控制下表达肝细胞生长因子的转基因小鼠，以研究其在肝细胞生长中的体内作用。这些小鼠的肝细胞表达作为自分泌生长因子的肝细胞生长因子水平增加。肝细胞生长因子是肝脏修复的有力刺激物;肝细胞生长因子转基因小鼠的肝脏在部分肝切除术后完全恢复所需时间的一半。这种转基因模型也使我们能够研究肝细胞生长因子表达的慢性效应。在几个月的观察中，白蛋白-肝细胞生长因子小鼠的肝细胞标记指数比野生型小鼠增加了一倍，肝DNA含量增加。为了确定肝细胞生长因子的中间信号通路，可能会调节这种增加的生长反应，我们检查了转基因小鼠的基因表达的变化，已知在肝再生过程中进行调节。我们发现，c-myc和c-jun mRNA的水平增加，在肝细胞生长因子转基因小鼠。在另外的实验中，增加的c-myc表达是增加的转录速率的结果，如在核运行和myc-CAT报告基因实验中所见。我们的结论是，肝细胞生长因子增加生长和修复过程时，在肝脏中长时间表达，c-myc和c-jun可能是肝细胞生长因子引起的肝细胞生长反应的重要中介。
Attention has recently been focused on hepatocyte growth factor as a major candidate factor in liver regeneration because it is the most potent known mitogen for hepatocytes in vitro. However, hepatocyte growth factor also displays diverse activities in vitro as scatter factor, as an epithelial morphogen, as a pluripotent mitogen and as a growth inhibitor. Consequently, we developed transgenic mice that expressed hepatocyte growth factor under the control of albumin regulatory sequences to examine its in vivo role in hepatocyte growth. Hepatocytes of these mice expressed increased levels of hepatocyte growth factor as an autocrine growth factor. Hepatocyte growth factor was a potent stimulus for liver repair; the livers of hepatocyte growth factor-transgenic mice recovered completely in half the time needed for their normal siblings after partial hepatectomy. This transgenic model also enabled us to study the chronic effects of hepatocyte growth factor expression. During several months of observation, the labeling index of hepatocytes in albumin-hepatocyte growth factor mice was doubled, and liver DNA content was increased compared with that in wild-type mice. To identify intermediate signaling pathways for hepatocyte growth factor that might regulate this increased growth response, we examined transgenic mice for changes in expression of genes that are known to be regulated during liver regeneration. We found that levels of c-myc and c-jun mRNA were increased in the hepatocyte growth factor-transgenic mice. In additional experiments the increased c-myc expression was the consequence of increased transcription rates as seen in nuclear run-on and myc-CAT reporter gene experiments. We conclude that hepatocyte growth factor increases growth and repair processes when expressed for long periods in the liver and that c-myc and c-jun may be important intermediaries in the hepatocyte growth response caused by hepatocyte growth factor.