title: DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway.
abstract: Exposure of hematopoietic cells to DNA-damaging agents induces cell-cycle arrest at G1 and G2/M checkpoints. Previously, it was shown that DNA damage-induced growth arrest of hematopoietic cells can be overridden by treatment with cytokine growth factors, such as erythropoietin (EPO) or interleukin-3 (IL-3). Here, the cytokine-activated signaling pathways required to override G1 and G2/M checkpoints induced by gamma-irradiation (gamma-IR) are characterized. Using factor-dependent myeloid cells stably expressing EPO receptor (EPO-R) mutants, it is shown that removal of a minimal domain required for PI-3K signaling abrogated the ability of EPO to override gamma-IR-induced cell-cycle arrest. Similarly, the ability of cytokines to override gamma-IR-induced arrest was abolished by an inhibitor of PI-3K (LY294002) or by overexpression of dominant-negative Akt. Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt. Thus, activation of a PI-3K/Akt signaling pathway is required for cytokine-dependent suppression of DNA-damage induced checkpoints. Together, these findings suggest a novel role for PI-3K/Akt pathways in the modulation of growth arrest responses to DNA damage in hematopoietic cells. (Blood. 2001;98:834-841)
authors.affiliation: Department of Pharmacology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Henry
authors.forename: J T
authors.initials: JT
authors.lastname: Lynch
authors.forename: A K
authors.initials: AK
authors.lastname: Eapen
authors.forename: F W
authors.initials: FW
authors.lastname: Quelle
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects; D002460:Cell Line; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation; D004921:Erythropoietin / Q000494:pharmacology; D005720:Gamma Rays; D006412:Hematopoietic Stem Cells / Q000502:physiology* / Q000528:radiation effects; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D017467:Receptors, Erythropoietin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004921:Erythropoietin; D007377:Interleukin-3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017467:Receptors, Erythropoietin