DNA Damage-Induced G1 Arrest in Hematopoietic Cells Is Overridden following Phosphatidylinositol 3-Kinase-Dependent Activation of Cyclin-Dependent Kinase 2

Alex K Eapen; Matthew K Henry; Dawn E Quelle; Frederick W Quelle

doi:10.1128/MCB.21.18.6113-6121.2001

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DNA Damage-Induced G1 Arrest in Hematopoietic Cells Is Overridden following Phosphatidylinositol 3-Kinase-Dependent Activation of Cyclin-Dependent Kinase 2

Journal article

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DNA Damage-Induced G1 Arrest in Hematopoietic Cells Is Overridden following Phosphatidylinositol 3-Kinase-Dependent Activation of Cyclin-Dependent Kinase 2

Alex K Eapen, Matthew K Henry, Dawn E Quelle and Frederick W Quelle

Molecular and cellular biology, Vol.21(18), pp.6113-6121

09/2001

DOI: 10.1128/MCB.21.18.6113-6121.2001

PMCID: PMC87328

PMID: 11509654

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Abstract

Exposure of hematopoietic cells to DNA-damaging agents induces p53-independent cell cycle arrest at a G1 checkpoint. Previously, we have shown that this growth arrest can be overridden by cytokine growth factors, such as erythropoietin or interleukin-3, through activation of a phosphatidylinositol 3-kinase (PI 3-kinase)/Akt-dependent signaling pathway. Here, we show that γ-irradiated murine myeloid 32D cells arrest in G1 with active cyclin D–cyclin-dependent kinase 4 (Cdk4) but with inactive cyclin E-Cdk2 kinases. The arrest was associated with elevated levels of the Cdk inhibitors p21Cip1 and p27Kip1, yet neither was associated with Cdk2. Instead, irradiation-induced inhibition of cyclin E-Cdk2 correlated with absence of the activating threonine-160 phosphorylation on Cdk2. Cytokine treatment of irradiated cells induced Cdk2 phosphorylation and activation, and cells entered into S phase despite sustained high-level expression of p21 and p27. Notably, the PI 3-kinase inhibitor, LY294002, completely blocked cytokine-induced Cdk2 activation and cell growth in irradiated 32D cells but not in nonirradiated cells. Together, these findings demonstrate a novel mechanism underlying the DNA damage-induced G1 arrest of hematopoietic cells, that is, inhibition of Cdk2 phosphorylation and activation. These observations link PI 3-kinase signaling pathways with the regulation of Cdk2 activity.

Cell Growth and Development

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Title: Subtitle: DNA Damage-Induced G1 Arrest in Hematopoietic Cells Is Overridden following Phosphatidylinositol 3-Kinase-Dependent Activation of Cyclin-Dependent Kinase 2
Creators: Alex K Eapen - Department of Pharmacology
Matthew K Henry - Department of Pharmacology
Dawn E Quelle - Department of Pharmacology
Frederick W Quelle - Department of Pharmacology
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.21(18), pp.6113-6121
DOI: 10.1128/MCB.21.18.6113-6121.2001
PMID: 11509654
PMCID: PMC87328
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Publisher: American Society for Microbiology
Language: English
Date published: 09/2001
Academic Unit: Pathology; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040546702771

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