| Akt/PKB (protein kinase B) is a multifunctional protein kinase that regulates a variety of cellular processes, including cell survival, cell proliferation, and glucose metabolism. Akt is hyperactivated in a variety of human cancers, implicating it as an oncogene. The ability of Akt to promote cell survival and cell proliferation is likely responsible for the oncogenic potential of Akt. Therefore, delineating the molecular mechanisms by which Akt antagonizes apoptosis (or programmed cell death) and drives cells through the cell cycle could provide valuable information for developing novel therapies to combat the oncogenic activity of Akt.;With respect to apoptosis, we demonstrate that Akt prevents the activation of the apoptosis-inducing proteins BAX and BAK at the mitochondria following growth factor withdrawal and BID induced apoptosis. BAX and BAK are critical regulators of mitochondrial cytochrome c release, a critical event in the progression of apoptosis. We provide further evidence that Akt may inhibit BAX/BAK activation and cytochrome c release by increasing the mitochondrial association of the glycolytic enzyme hexokinase Hexokinase, like Akt, can inhibit apoptosis, cytochrome c release, and BAX activation. In addition, enforced dissociation of hexokinase from the mitochondria accelerates the kinetics of apoptosis and cytochrome c release, and diminishes the ability of Akt to antagonize these processes. Interestingly, enforced dissociation of hexokinase from the mitochondria induced cytochrome c release from the mitochondria in the absence of BAX and BAK, contradicting the dogma that BAX and BAK are absolutely required for cytochrome c release to occur.;With respect to cell cycle progression, we demonstrate that Akt can drive the G1 to S phase cell cycle transition by a novel mechanism, independent of phosphorylation and inhibition of the cell cycle regulatory transcription factor Foxo1/FKHR. In addition to regulating the G1 to S phase transition, we 1demonstrate that Akt can also regulate the G2 to M phase transition by overriding DNA damage induced G2 phase arrest. |
