Divide, differentiate or die? Novel molecular mechanisms underlying PKB-mediated regulation of cell fate decisions

Homeostasis of the hematopoietic system requires tight control of proliferation, differentiation and survival of progenitor cells. Combinations of cytokines acting on these cells initiate specific developmental programs through activation of distinct downstream signal-transduction pathways. Over the last two decades it has become evident that the phosphatidylinostol 3-kinse (PI3K)/ protein kinase B (PKB/c-akt) signaling module plays a critical role in a plethora of cellular processes. Evidence also suggests that PI3K/ PKB signaling may also play a role in regulating blood cell production and the PI3K/PKB axis is often aberrantly regulated in hematopoietic malignancies. More recently it has been demonstrated that members of the FOXO subfamily of Forkhead transcription factors play an important role in conveying PI3K/PKB activation to cell-type specific changes in transcriptional programs. However, despite an increased awareness of the importance of PI3K/PKB/FOXO function in cellular homeostasis and transformation, the specific underlying molecular mechanisms remain unclear.
We have recently identified several novel intracellular mechanisms mediating PI3K/PKB/FOXO regulation of progenitor cell proliferation, differentiation and survival. To this end we developed a cell-based drug inducible activation system for PI3K, PKB and FOXO3. This has allowed us to investigate the effects of independently activating these molecules on cellular function. Utilizing a novel phosphoproteomics screen we have been able to show that the elongation initiation factor eIF4B is a bona fide PKB substrate. This potentially allows PI3K/PKB to control the translation of specific mRNA transcripts. We also observed that, in contrast to PI3K, chronic PKB activation leads to increased intracellular ROS production resulting in increased FOXO3 expression. Surprisingly, this ultimately leads to quiescence and induction of programmed cell death. Finally, in a microarray analysis we identified the transcriptional repressor ID1 as a direct FOXO target gene. ID1 expression is known to be significantly correlated with cancer progression and prognosis, and could potentially be exploited as a therapeutic target. We found that ID1 expression is strongly repressed by FOXO activation and conversely it is induced by PI3K/PKB signaling. We have also been able to show that this is critical for the maintenance of the leukemic phenotype in chronic myeloid leukemia.
Taken together these data provide novel insights into the molecular mechanisms by which the PI3K/PKB/FOXO signaling module can impinge on cellular homeostasis, thereby regulating cell fate decisions, and if uncontrolled can lead to the development of neoplasia.