Summary Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoforms inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated combined Akt1 and Akt2 deletion induced rapid mortality. Akt2−/− mice survived hepatic Akt1 deletion but all develop spontaneous hepatocellular carcinoma (HCC), which is associated with FoxO-dependent liver injury and inflammation. The gene expression signature of HCC bearing livers is similar to aggressive human HCC. Consistently, neither Akt1−/− nor Akt2−/− mice are resistant to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2−/− mice display high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC.

Akt is perhaps the most frequently activated oncoprotein in human cancers. Overriding cell cycle checkpoint in combination with the inhibition of apoptosis are two principal requirements for predisposition to cancer. Here we show that the activation of Akt is sufficient to promote these two principal processes, by inhibiting Chk1 activation with concomitant inhibition of apoptosis. These activities of Akt cannot be recapitulated by the knockdown of Chk1 alone or by overexpression of Bcl2. Rather the combination of Chk1 knockdown and Bcl2 overexpression is required to recapitulate Akt activities. Akt was shown to directly phosphorylate Chk1. However, we found that Chk1 mutants in the Akt phosphorylation sites behave like wildtype Chk1 in mediating G2 arrest, suggesting that the phosphorylation of Chk1 by Akt is either dispensable for Chk1 activity or insufficient by itself to exert an effect on Chk1 activity. Here we report a new mechanism by which Akt affects G2 cell cycle arrest. We show that Akt inhibits BRCA1 function that induces G2 cell cycle arrest. Akt prevents the translocation of BRCA1 to DNA damage foci and, thereby, inhibiting the activation of Chk1 following DNA damage.The serine/threonine kinase Akt is perhaps the most frequently hyperactivated oncoprotein in human cancer (1, 2). However, the reasons behind this frequent hyperactivation are not fully explored. One of the most established consequences of Akt activation is inhibition of apoptosis. Inhibition of apoptosis is a critical step in the process of tumorigenesis and is a prerequisite for the genetic instability occurring during this process. Genetic instability that increases mutation rate, and that is associated with predisposition to cancer, is usually acquired through the abrogation of cell cycle checkpoints. However, the abrogation of cell cycle checkpoints by itself could elicit cell death as mechanism to eliminate cells with damaged DNA. Therefore, the inhibition of cell death is required in conjunction with deregulated cell cycle checkpoint to increase mutation rate during tumorigenesis. Certain genetic lesions could provide both cell cycle checkpoint abrogation and inhibition of apoptosis. The best example of such genetic lesion is the inactivation of p53 that overcomes cell cycle checkpoints with concomitant prevention of the elicited apoptosis, which could explain the frequent inactivation of p53 in cancer cells (3, 4). Our previous results suggest that, by analogy to p53 inactivation, the frequent activation of Akt in cancer cells could elicit both inhibition of apoptosis and abrogation of a G2 cell cycle checkpoint in a p53-independent manner (5). However, the mechanism by which Akt exerts its effect on the G2 cell cycle checkpoint is largely unknown.The p53-independent G2 cell cycle checkpoint following genotoxic stress is mediated by the cell cycle checkpoint protein Chk1. Upon DNA damage, the PI3 kinase-like kinases, ATM, ATR, and DNA-PK are activated and phosphorylate histone H2AX. The phosphorylated H2AX (␥H2AX) mediates the ...

Summary Akt is frequently activated in human cancers. However, it is unknown whether systemic inhibition of a single Akt isoform, could regress cancer progression in cancers that are not driven by Akt activation. We systemically deleted Akt1, after tumor onset, in p53−/− mice, which develop tumors independently of Akt activation. Systemic Akt1 deletion regresses thymic lymphoma in p53−/− mice emulating p53 restoration. Furthermore, pharmacological inhibition of Akt selectively kills thymic lymphoma cells and not primary thymocytes. Mechanistically, Akt1 inhibition in p53−/− thymic lymphoma inhibits Skp2 expression, and induces FasL, which is the primary cause of cell death. Skp2 exerts resistance to cell death by antagonizing the induction of FasL and reducing FAS expression, which is linked to cyclin D1 expression. The results established a new paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation, and a new mechanism of cell survival by Skp2.