p53-dependent growth arrest and induction of p21

in Greek mythology, one of Hercules’ labors was to slay the Hydra. The task seems impossible, as the creature was a multi-headed monster with the ability to grow two new heads when one was cleaved off. Oncologists face a similar daunting task in eliminating malignant cells, as each cancer appears to have its own Hydra protecting it. The suppression of the Forkhead box class O (FOXO) family of transcription factors is a common event in many cancers, including acute leukemias. FOXO3A can serve as a tumor suppressor, as it positively regulates genes that promote apoptosis (e.g., Bim, FAs ligand) and cell cycle arrest (p21 and p27).1,2 FOXO3A phosphorylation results in the ubiquitination, nuclear expulsion and proteolysis of the transcription factor.2-4 inactivation of FOXO3A is complex, as the mechanism involves a number of different survival kinases, including protein kinase B (AKT), iκB kinase b (iKKβ) and extracellular receptor kinase (eRK). Further complicating matters, each kinase recognizes different sites, so suppression of FOXO3A occurs at multiple levels. Of the FOXO3A kinases, the majority of focus is on AKT. such attention is logical, as aberrant activation of AKT by mutation of upstream regulators is common in many cancers.5 Mutations that induce AKT activation involve inactivation of negative regulators, such phosphatase and Tensin homolog (PTen), or constitutive activation of positive AKT regulators, such as Phosphoinositide-3 kinase (Pi3 Kinase), rat sarcoma (RAs) and Fms-like tyrosine kinase receptor-3 (FLT-3). The FLT-3 internal tandem duplication mutation (FLT-3iTD) is an especially poor prognostic factor for acute myeloid leukemia (AML) patients. Kornblau and colleagues recently demonstrated that phosphorylation of FOXO3A is an adverse prognostic factor for survival and Cell Cycle News & Views