Transgenic Overexpression of Insulin Receptor Substrate 1 in Hepatocytes Enhances Hepatocellular Proliferation in Young Mice Only

Overview

Journal Hepatol Res

Specialty Gastroenterology

Date 2008 Jul 18

PMID 18631251

Citations 2

Authors

Leonhard Mohr

Kakoli Banerjee

Manuela Kleinschmidt

Maria Matilde Bartolome Rodriguez

Jack R Wands

Affiliations

Soon will be listed here.

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.

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