Journal article
DNA damage–induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway
Blood, Vol.98(3), pp.834-841
08/01/2001
DOI: 10.1182/blood.V98.3.834
PMID: 11468186
Abstract
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 γ-irradiation (γ-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 γ-IR–induced cell-cycle arrest. Similarly, the ability of cytokines to override γ-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.
Details
- Title: Subtitle
- DNA damage–induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway
- Creators
- Matthew K Henry - From the Department of Pharmacology and the Immunology Graduate Program, The University of Iowa College of Medicine, Iowa CityJeffrey T Lynch - From the Department of Pharmacology and the Immunology Graduate Program, The University of Iowa College of Medicine, Iowa CityAlex K Eapen - From the Department of Pharmacology and the Immunology Graduate Program, The University of Iowa College of Medicine, Iowa CityFrederick W Quelle - From the Department of Pharmacology and the Immunology Graduate Program, The University of Iowa College of Medicine, Iowa City
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.98(3), pp.834-841
- DOI
- 10.1182/blood.V98.3.834
- PMID
- 11468186
- NLM abbreviation
- Blood
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 08/01/2001
- Academic Unit
- Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040489002771
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