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These studies show the mixture of activated AKT and RAS in Ganetespib cells in a less comprehensive senescence program than does activated RAS alone. Mechanism of antagonism of senescence by activated AKT We next wanted to know the mechanism by which activated AKT1 antagonizes aspects of RASG12V induced senescence. Because AKT1 stimulates mTOR and mTOR is just a effective inhibitor of autophagy, we hypothesized that activated AKT1 suppresses RASG12V induced autophagy by activation of mTOR. Consistent with this idea, while in the presence of activated RAS, activated AKT1 activated mTOR, as judged by phosphorylation of mTOR substrates, 4EBP1 and p70S6K. Regarding SAHF, we previously showed that activated RAS induces HIRA localization to PML bodies and development of SAHF through its ability to activate GSK3B. In comparison, AKT is famous to specifically inhibit GSK3B through Cholangiocarcinoma inhibitory phosphorylation on serine 9. Consequently, we hypothesized that mAKT1s ability to stop RASG12Vinduced SAHF development might rely on its ability to phosphorylate and inhibit GSK3B. Consistent with this notion, in cells coexpressing activated RAS and AKT, GSK3B was heavily phosphorylated on 9. This suggests that RASG12Vinduced activation of GSK3B is finished ridden by mAKT1 induced inhibition of GSK3B. To test our hypothesis further, we expressed activated AKT1 with or without a nonphosphorylatable mutant of GSK3B, and found that, even in the presence of activated AKT1, GSK3BS9A had been able to induce both localization of HIRA to PML bodies and SAHF formation. We confirmed proper expression of GSK3BS9A and activated AKT by western blotting. These are in keeping with the notion that activated AKT1 inhibits HIRA CX-4945 activation and formation of SAHF, at the least partly, through phosphorylation and inhibition of GSK3B. Underscoring the significance of AKT1 mediated GSK3B phosphorylation in human cancer, we discovered that in a pancreatic cancer Tissue MicroArray the amount of GSK3BpS9 correlated with poor patient survival, independent of tumor size, tumor level, perineural invasion, resection margin involvement and lymph node status. Phosphorylation and activation of AKT1 and its downstream effector, mTOR, and mixed phosphorylation and activation of AKT1 and mTOR likewise correlated with poor disease consequence, also emphasizing the significance of activated AKT1 in this disease. AKT pathway activation antagonizes RAS induced proliferation charge to drive tumorigenesis in the mouse pancreas We next wanted to check whether activation of PIK3CA/AKT signaling is able to reduce activated RAS induced senescence and accelerate tumefaction formation in vivo. To achieve this, we utilized a mouse model in which expression of activated RAS is restricted to the cells of the pancreas, by virtue of a conditional RAS allele at its normal genomic locus that can be activated by Cre mediated recombination, and pancreas distinct expression of Cre recombinase in check of a PDX1 promoter.