PMID- 8930401
OWN - NLM
STAT- MEDLINE
DCOM- 19970227
LR  - 20161123
IS  - 1044-9523 (Print)
IS  - 1044-9523 (Linking)
VI  - 7
IP  - 11
DP  - 1996 Nov
TI  - Hepatocyte growth factor/scatter factor overexpression induces growth, abnormal 
      development, and tumor formation in transgenic mouse livers.
PG  - 1513-23
AB  - To investigate the in vivo role of hepatocyte growth factor/scatter factor 
      (HGF/SF) in liver function, we generated transgenic mice using a mouse HGF/SF 
      cDNA under the control of the mouse metallothionein gene promoter and 5'/3' 
      flanking sequences. In adult HGF/SF transgenic mice, liver weight as a percentage 
      of total body weight was at least twice that of wild-type mice. Comparison of 
      transgenic and control liver morphology revealed dramatic heterogeneity in the 
      size and appearance of hepatocytes as a distinctive feature of HGF/SF 
      overexpression. Transgenic livers exhibited a significant increase in the number 
      of small hepatocytes with a 2N DNA content, accounting for the observed increase 
      in liver mass. The DNA labeling index of hepatocytes increased 11-fold at 4 weeks 
      of age, when liver enlargement first became apparent, and was still elevated 
      about 5-fold in adult HGF/SF transgenic mice. Moreover, hepatocytes isolated by 
      perfusion of transgenic livers doubled every 2 days in culture, whereas little or 
      no growth was observed with isolated control hepatocytes. The mechanistic basis 
      of hepatocyte proliferation was elucidated as the chronic activation of the c-met 
      proto-oncogene product. Met and substrates such as phosphatidylinositol 3-kinase, 
      Src homology and collagen-like, pp60c-src, focal adhesion kinase p125FAK, and 
      paxillin were associated with tyrosine-phosphorylated complexes in a hepatocyte 
      cell line established from the transgenic liver. This proliferative stimulus 
      triggered the formation of hepatocellular adenomas and/or carcinomas in most 
      transgenic mice > or = 1.5 years of age. Finally, the rate of transgenic mouse 
      liver regeneration was increased 3-fold over control livers following partial 
      hepatectomy.
FAU - Sakata, H
AU  - Sakata H
AD  - Laboratory of Cellular and Molecular Biology, National Cancer Institute, 
      Bethesda, Maryland 20892, USA.
FAU - Takayama, H
AU  - Takayama H
FAU - Sharp, R
AU  - Sharp R
FAU - Rubin, J S
AU  - Rubin JS
FAU - Merlino, G
AU  - Merlino G
FAU - LaRochelle, W J
AU  - LaRochelle WJ
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cell Growth Differ
JT  - Cell growth & differentiation : the molecular biology journal of the American 
      Association for Cancer Research
JID - 9100024
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Shc Signaling Adaptor Proteins)
RN  - 0 (Shc1 protein, mouse)
RN  - 0 (Src Homology 2 Domain-Containing, Transforming Protein 1)
RN  - 42HK56048U (Tyrosine)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src))
RN  - EC 2.7.10.2 (Ptk2 protein, mouse)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - *Adaptor Proteins, Vesicular Transport
MH  - Age Factors
MH  - Animals
MH  - Cell Adhesion Molecules/analysis
MH  - Cell Division
MH  - Cell Line
MH  - DNA/analysis
MH  - Female
MH  - Focal Adhesion Kinase 1
MH  - Focal Adhesion Protein-Tyrosine Kinases
MH  - Gene Expression
MH  - Hepatocyte Growth Factor/genetics/*physiology
MH  - Liver/*growth & development/pathology/ultrastructure
MH  - Liver Neoplasms/*genetics
MH  - Liver Regeneration
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Organ Size
MH  - Phosphatidylinositol 3-Kinases
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/analysis
MH  - Protein-Tyrosine Kinases/analysis
MH  - Proteins/analysis
MH  - Proto-Oncogene Proteins c-met
MH  - Proto-Oncogene Proteins pp60(c-src)/analysis
MH  - RNA, Messenger/analysis
MH  - Receptor Protein-Tyrosine Kinases/metabolism
MH  - Shc Signaling Adaptor Proteins
MH  - Src Homology 2 Domain-Containing, Transforming Protein 1
MH  - Tyrosine/metabolism
EDAT- 1996/11/01 00:00
MHDA- 1996/11/01 00:01
CRDT- 1996/11/01 00:00
PHST- 1996/11/01 00:00 [pubmed]
PHST- 1996/11/01 00:01 [medline]
PHST- 1996/11/01 00:00 [entrez]
PST - ppublish
SO  - Cell Growth Differ. 1996 Nov;7(11):1513-23.