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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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