Wiedmann Marcus, Tamaki Seishu, Silberman Rebecca, de la Monte Suzanne M, Cousens Leslie, Wands Jack R
Department of Medicine, Liver Research Center, Rhode Island Hospital, Brown University School of Medicine, 55 Claverick Street 4th floor, Providence, RI 02903, USA.
J Hepatol. 2003 Jun;38(6):803-10. doi: 10.1016/s0168-8278(03)00117-x.
BACKGROUND/AIMS: Insulin- and insulin growth factor-1 stimulated signaling through the insulin receptor substrate-1 (IRS-1) promotes hepatocellular proliferation and survival. IRS-1 over-expression in transgenic (Tg) mouse livers caused constitutive activation of Erk mitogen activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) resulting in significantly increased levels of DNA synthesis and larger hepatic masses relative to non-transgenic (non-Tg) littermates. However, the livers eventually ceased to grow but remained approximately 25% larger than non-Tg livers. We hypothesized that this growth homeostasis was achieved by parallel activation of pro-apoptosis pathways.
Since Fas-mediated apoptosis is a common mechanism of hepatocyte destruction, we investigated the potential role of Fas receptor as a regulator of hepatic mass in IRS-1 transgenic mice.
Significantly increased Fas-receptor levels were detected in the livers of IRS-1 Tg compared to non-Tg mice by Western blot analysis. Functional activation of Fas-receptor in IRS-1 Tg livers was demonstrated by increased hepatocellular apoptosis caused by intravenous injection of anti-Fas (Jo-2).
These findings suggest that the increased growth caused by IRS-1 over-expression is balanced by constitutive activation of pro-death mechanisms. Failure of the IRS-1 Tg mice to develop liver cancer may be due to preservation of pro-growth, pro-death homeostasis mechanisms.
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