Constitutive over-expression of the insulin receptor substrate-1 causes functional up-regulation of Fas receptor.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Wiedmann
Marcus
M
Department of Medicine, Liver Research Center, Rhode Island Hospital, Brown University School of Medicine, 55 Claverick Street 4th floor, Providence, RI 02903, USA.
Tamaki
Seishu
S
Silberman
Rebecca
R
de la Monte
Suzanne M
SM
Cousens
Leslie
L
Wands
Jack R
JR
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D020287:In Situ Nick-End Labeling; D055504:Insulin Receptor Substrate Proteins; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D019014:fas Receptor