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Molecular and Cellular Biology, November 2000, p. 8018-8025, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Proapoptotic p53-Interacting Protein 53BP2 Is Induced by UV Irradiation but Suppressed by p53

Charles D. Lopez,1,* Yi Ao,2 Larry H. Rohde,2,dagger Tomas D. Perez,2 Daniel J. O'Connor,3 Xin Lu,3 James M. Ford,1,4 and Louie Naumovski2

Divisions of Medical Oncology1 and Genetics,4 Department of Medicine, and Division of Hematology/Oncology, Department of Pediatrics,2 Stanford University School of Medicine, Stanford, California 94305, and Ludwig Institute for Cancer Research, Imperial College of Medicine at St. Mary's, London W2 1PG, United Kingdom3

Received 13 January 2000/Returned for modification 17 March 2000/Accepted 3 August 2000

p53 is an important mediator of the cellular stress response with roles in cell cycle control, DNA repair, and apoptosis. 53BP2, a p53-interacting protein, enhances p53 transactivation, impedes cell cycle progression, and promotes apoptosis through unknown mechanisms. We now demonstrate that endogenous 53BP2 levels increase following UV irradiation induced DNA damage in a p53-independent manner. In contrast, we found that the presence of a wild-type (but not mutant) p53 gene suppressed 53BP2 steady-state levels in cell lines with defined p53 genotypes. Likewise, expression of a tetracycline-regulated wild-type p53 cDNA in p53-null fibroblasts caused a reduction in 53BP2 protein levels. However, 53BP2 levels were not reduced if the tetracycline-regulated p53 cDNA was expressed after UV damage in these cells. This suggests that UV damage activates cellular factors that can relieve the p53-mediated suppression of 53BP2 protein. To address the physiologic significance of 53BP2 induction, we utilized stable cell lines with a ponasterone A-regulated 53BP2 cDNA. Conditional expression of 53BP2 cDNA lowered the apoptotic threshold and decreased clonogenic survival following UV irradiation. Conversely, attenuation of endogenous 53BP2 induction with an antisense oligonucleotide resulted in enhanced clonogenic survival following UV irradiation. These results demonstrate that 53BP2 is a DNA damage-inducible protein that promotes DNA damage-induced apoptosis. Furthermore, 53BP2 expression is highly regulated and involves both p53-dependent and p53-independent mechanisms. Our data provide new insight into 53BP2 function and open new avenues for investigation into the cellular response to genotoxic stress.

* Corresponding author. Mailing address: Department of Medicine, Division of Medical Oncology, 269 Campus Dr., CCSR, Stanford University School of Medicine, Stanford, CA 94305. Phone: (650) 498-5221. Fax: (650) 736-0195. E-mail: cdlopez{at}leland.stanford.edu.

dagger Present address: School of Natural and Applied Sciences, University of Houston-Clear Lake, Houston, TX 77058.

Molecular and Cellular Biology, November 2000, p. 8018-8025, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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