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Molecular and Cellular Biology, September 2001, p. 6113-6121, Vol. 21, No. 18
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
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
-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.
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