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Molecular and Cellular Biology, June 2000, p. 4210-4223, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

p53 Regulation of G2 Checkpoint Is Retinoblastoma Protein Dependent

Patricia M. Flatt, Luo Jia Tang, Caroline D. Scatena, Suzanne T. Szak, and Jennifer A. Pietenpol*

Department of Biochemistry, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Received 30 September 1999/Returned for modification 10 November 1999/Accepted 15 March 2000

In the present study, we investigated the role of p53 in G2 checkpoint function by determining the mechanism by which p53 prevents premature exit from G2 arrest after genotoxic stress. Using three cell model systems, each isogenic, we showed that either ectopic or endogenous p53 sustained a G2 arrest activated by ionizing radiation or adriamycin. The mechanism was p21 and retinoblastoma protein (pRB) dependent and involved an initial inhibition of cyclin B1-Cdc2 activity and a secondary decrease in cyclin B1 and Cdc2 levels. Abrogation of p21 or pRB function in cells containing wild-type p53 blocked the down-regulation of cyclin B1 and Cdc2 expression and led to an accelerated exit from G2 after genotoxic stress. Thus, similar to what occurs in p21 and p53 deficiency, pRB loss can uncouple S phase and mitosis after genotoxic stress in tumor cells. These results indicate that similar molecular mechanisms are required for p53 regulation of G1 and G2 checkpoints.

* Corresponding author. Mailing address: Vanderbilt University School of Medicine, Department of Biochemistry, 652 Medical Research Building II, Nashville, TN 37232-6305. Phone: (615) 936-1512. Fax: (615) 936-2294. E-mail: pietenpol{at}toxicology.mc.vanderbilt.edu.

Molecular and Cellular Biology, June 2000, p. 4210-4223, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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