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Molecular and Cellular Biology, September 2001, p. 6113-6121, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6113-6121.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Alex K. Eapen,1 Matthew K. Henry,1 Dawn E. Quelle,1,2 and Frederick W. Quelle1,3,*

Department of Pharmacology,1 Molecular Biology Program,2 and Immunology Program,3 The University of Iowa College of Medicine, Iowa City, Iowa 52242

Received 1 February 2001/Returned for modification 13 March 2001/Accepted 18 June 2001

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 gamma -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.

* Corresponding author. Mailing address: Department of Pharmacology, 2-210 Bowen Science Bldg., University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 335-8539. Fax: (319) 335-8930. E-mail: frederick-quelle{at}uiowa.edu.

Molecular and Cellular Biology, September 2001, p. 6113-6121, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6113-6121.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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