Fig. 1. An intact PI3K pathway is required for Hgf-induced Mdm2 translocation. (A) Upon Hgf stimulation, wild-type (+/+) Met induces Mdm2 translocation from the cytoplasm into the nucleus of cultured primary embryonic hepatocytes. By contrast, Met^2P, which has intact PI3K activity but reduced Akt signaling (met^2P/2P), does not trigger Mdm2 translocation. (B) Quantitative analysis of Mdm2 translocation in wild-type (+/+) and mutant (2P/2P) embryonic hepatocytes. Mdm2 translocation in wild-type hepatocytes is abolished in the presence of the PI3K inhibitor LY 294002 (10 µM). (C) In vivo inactivation of p53 restores hepatocyte survival in met^2P/2P mutant embryos. TUNEL staining of liver cryosections from E12.5 wild-type (+/+), met^2P/2P treated (met^2P/2P+PFT) or not (met^2P/2P) with the p53 inhibitor pifithrin- and double-homozygous met^2P/2P; p53^-/- embryos. (D) Quantitative analysis of TUNEL-positive cells in E12.5 liver sections of the indicated genotypes. The proportion of apoptotic cells is represented as fold increase compared with wild-type livers. The numbers of embryos analyzed in these studies are indicated (n). Arrows indicate nuclei. ^**P<0.001.