Regulation of p38, PKC/Foxo3a/p73 signaling network by GTP during erythroid differentiation in chronic myelogenous leukemia.

It is well established that Foxo3a is a fundamental module of signal transduction pathways regulating erythropoiesis; however, precise mechanism which regulates its physiological function still remains unclear. Here, our results revealed that the nuclear localization and stability of Foxo3a were modulated by the physical interaction of PKC and p38 signaling elements and that direct interactions led to phosphorylation of threonine residue(s) in Foxo3a. In addition, our findings revealed that the sequential activity of Foxo3a by guanosine 5'-triphosphate can impede cellular proliferation and suppress p73 expression as oncoprotein in K562 cells; thus identifying Foxo3a as a tumor suppressor in these p53 null cells. However, down-regulation of Foxo3a-dependent p73 expression causes cell differentiation along the erythroid lineage. Collectively, our findings suggest that restoration of Foxo3a function by pharmacological agents under the influence of specific activated protein kinases might constitute a potential therapeutic strategy for combating the CML disease.