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Molecular and Cellular Biology, January 2008, p. 258-268, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01536-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

p27^kip1 Deficiency Impairs G₂/M Arrest in Response to DNA Damage, Leading to an Increase in Genetic Instability

Shannon R. Payne,^1, Shulin Zhang,² Karen Tsuchiya,¹ Russell Moser,¹ Kay E. Gurley,¹ Gary Longton,¹ Johan deBoer,² and Christopher J. Kemp^1*

Fred Hutchinson Cancer Research Center, Seattle, Washington,¹ University of Victoria, Victoria, British Columbia, Canada²

Received 22 August 2007/ Returned for modification 19 September 2007/ Accepted 9 October 2007

p27^kip1 is a cyclin-dependent kinase inhibitor and a tumor suppressor. In some tumors, p27 suppresses tumor growth by inhibition of cell proliferation. However, this is not universally observed, implying additional mechanisms of tumor suppression by p27. p27-deficient mice are particularly susceptibility to genotoxin-induced tumors, suggesting a role for p27 in the DNA damage response. To test this hypothesis, we measured genotoxin-induced mutations and chromosome damage in p27-deficient mice. Both p27^+/– and p27^–/– mice displayed a higher N-ethyl-N-nitrosourea-induced mutation frequency in the colon than p27^+/+ littermates. Furthermore, cells from irradiated p27-deficient mice exhibited a higher number of chromatid breaks and showed modestly increased micronucleus formation compared to cells from wild-type littermates. To determine if this mutator phenotype was related to the cell cycle-inhibitory function of p27, we measured cell cycle arrest in response to DNA damage. Both normal and tumor cells from p27-deficient mice showed impaired G₂/M arrest following low doses of ionizing radiation. Thus, p27 may inhibit tumor development through two mechanisms. The first is by reducing the proliferation of cells that have already sustained an oncogenic lesion. The second is by transient inhibition of cell cycle progression following genotoxic insult, thereby minimizing chromosome damage and fixation of mutations.

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* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center C1-015, 1100 Fairview Ave. N., Seattle, WA 90109-1024. Phone: (206) 667-4252. Fax: (206) 667-5815. E-mail: cjkemp{at}fhcrc.org

Published ahead of print on 22 October 2007.

Present address: Epigenomics, Inc., Seattle, WA.

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Molecular and Cellular Biology, January 2008, p. 258-268, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01536-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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