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Molecular and Cellular Biology, September 1999, p. 5872-5881, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The G2 Checkpoint Is Maintained by Redundant Pathways

Tina M. Passalaris,1 Jennifer A. Benanti,1,2 Lindy Gewin,1,2 Tohru Kiyono,1,3 and Denise A. Galloway1,*

Program in Cancer Biology, Fred Hutchinson Cancer Research Center,1 and Molecular and Cellular Biology Graduate Program, University of Washington and Fred Hutchinson Cancer Research Center,2 Seattle, Washington 98109-1024, and Laboratory of Viral Oncology, Aichi Cancer Center, Research Institute, Chikusa-ku, Nagoya 464-0021, Japan3

Received 21 January 1999/Returned for modification 4 March 1999/Accepted 27 May 1999

While p53 activity is critical for a DNA damage-induced G1 checkpoint, its role in the G2 checkpoint has not been compelling because cells lacking p53 retain the ability to arrest in G2 following DNA damage. Comparison between normal human foreskin fibroblasts (HFFs) and HFFs in which p53 was eliminated by transduction with human papillomavirus type 16 E6 showed that treatment with adriamycin initiated arrest in G2 with active cyclin B/CDC2 kinase, regardless of p53 status. Both E6-transduced HFFs and control (LXSN)-transduced cells maintained a prolonged arrest in G2; however cells with functional p53 extinguished cyclin B-associated kinase activity. Down regulation was mediated by p53-dependent transcriptional repression of the CDC2 and cyclin B promoters. In contrast, cells lacking p53 showed a prolonged G2 arrest despite high levels of cyclin B/CDC2 kinase activity, at least some of which translocated into the nucleus. Furthermore, the G2 checkpoint became attenuated as p53-deficient cells aged in culture. Thus, at late passage, E6-transduced HFFs entered mitosis following DNA damage, whereas the age-matched parental HFFs sustained a G2 arrest. These results indicate that normal cells have p53-independent pathways to maintain DNA damage-induced G2 arrest, which may be augmented by p53-dependent functions, and that cells lacking p53 are at greater risk of losing the pathway that protects against aneuploidy.

* Corresponding author. Mailing address: Program in Cancer Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., C1-015, Seattle, WA 98109-1024. Phone: (206) 667-4500. Fax: (206) 667-5815. E-mail: dgallowa{at}fhcrc.org.

Molecular and Cellular Biology, September 1999, p. 5872-5881, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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