Transgenic overexpression of insulin receptor substrate 1 in hepatocytes enhances hepatocellular proliferation in young mice only.
| Autor: | Mohr L; Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA., Banerjee K, Kleinschmidt M, Bartolomé Rodríguez MM, Wands JR |
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| Jazyk: | angličtina |
| Zdroj: | Hepatology research : the official journal of the Japan Society of Hepatology [Hepatol Res] 2008 Dec; Vol. 38 (12), pp. 1233-40. Date of Electronic Publication: 2008 Jul 04. |
| DOI: | 10.1111/j.1872-034X.2008.00396.x |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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