title: Transgenic overexpression of insulin receptor substrate 1 in hepatocytes enhances hepatocellular proliferation in young mice only.
abstract: OBJECTIVE
  The insulin receptor substrate-1 (IRS-1) is a multisite docking protein which plays a central role in the signal transduction of growth factors such as insulin and insulin-like growth factors (IGF-1 and IGF-2). It is found to be frequently overexpressed in human hepatocellular carcinoma (HCC).
  
  
  METHODS
  To study IRS-1 overexpression in hepatocytes in vivo, transgenic mice overexpressing IRS-1 exclusively in hepatocytes were created, showing enhanced hepatocyte proliferation in young animals. In the present study, the phenotype of IRS-1 transgenic animals was characterized over a period of two years. The livers of transgenic and control mice were analyzed for IRS-1 expression and phosphorylation, activation of the downstream mitogen-activated protein kinase (MAPK) cascade and phosphatidylinositol 3' kinase (PI3'K) and macroscopical and histological abnormalities.
  
  
  RESULTS
  The enhanced hepatocyte proliferation observed in young IRS-1 transgenic animals was no longer detectable in adult mice. Despite constitutive overexpression and phosphorylation of IRS-1, MAPK- and IRS-1-associated PI3'K activity were significantly reduced in older transgenic mice. Furthermore, no premalignant lesions or HCC were detected in IRS-1 transgenic animals up to the age of 24 months.
  
  
  CONCLUSIONS
  Therefore, additional mechanisms such as enhanced growth factor expression or impaired negative feedback control mechanisms may augment IRS-1 overexpression in human hepatocarcinogenesis.
authors.affiliation: Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Leonhard
authors.initials: L
authors.lastname: Mohr
authors.forename: Kakoli
authors.initials: K
authors.lastname: Banerjee
authors.forename: Manuela
authors.initials: M
authors.lastname: Kleinschmidt
authors.forename: María Matilde
authors.initials: MM
authors.lastname: Bartolomé Rodríguez
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands