Transgenic overexpression of insulin receptor substrate 1 in hepatocytes enhances hepatocellular proliferation in young mice only

Abstract

Aim: 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.