title: Regulation of p38, PKC/Foxo3a/p73 signaling network by GTP during erythroid differentiation in chronic myelogenous leukemia.
abstract: 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.
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Meshkini
authors.forename: Razieh
authors.initials: R
authors.lastname: Yazdanparast
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D041905:Erythroid Cells / Q000187:drug effects* / Q000473:pathology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D006160:Guanosine Triphosphate; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases