Proapoptotic p53-interacting protein 53BP2 is induced by UV irradiation but suppressed by p53

Charles Lopez, Y. Ao, L. H. Rohde, T. D. Perez, D. J. O'Connor, X. Lu, J. M. Ford, L. Naumovski

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8018-8025
Number of pages8
JournalMolecular and Cellular Biology
Volume20
Issue number21
DOIs
StatePublished - 2000
Externally publishedYes

Fingerprint

DNA Damage
Complementary DNA
Apoptosis
Tetracycline
Proteins
Cell Line
Antisense Oligonucleotides
p53 Genes
Cell Cycle Checkpoints
DNA Repair
Transcriptional Activation
Cell Cycle
Fibroblasts
Genotype

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Proapoptotic p53-interacting protein 53BP2 is induced by UV irradiation but suppressed by p53. / Lopez, Charles; Ao, Y.; Rohde, L. H.; Perez, T. D.; O'Connor, D. J.; Lu, X.; Ford, J. M.; Naumovski, L.

In: Molecular and Cellular Biology, Vol. 20, No. 21, 2000, p. 8018-8025.

Research output: Contribution to journalArticle

Lopez, C, Ao, Y, Rohde, LH, Perez, TD, O'Connor, DJ, Lu, X, Ford, JM & Naumovski, L 2000, 'Proapoptotic p53-interacting protein 53BP2 is induced by UV irradiation but suppressed by p53', Molecular and Cellular Biology, vol. 20, no. 21, pp. 8018-8025. https://doi.org/10.1128/MCB.20.21.8018-8025.2000
Lopez, Charles ; Ao, Y. ; Rohde, L. H. ; Perez, T. D. ; O'Connor, D. J. ; Lu, X. ; Ford, J. M. ; Naumovski, L. / Proapoptotic p53-interacting protein 53BP2 is induced by UV irradiation but suppressed by p53. In: Molecular and Cellular Biology. 2000 ; Vol. 20, No. 21. pp. 8018-8025.
@article{f1a71065f3f447c5876e9a5d684b57b3,
title = "Proapoptotic p53-interacting protein 53BP2 is induced by UV irradiation but suppressed by p53",
abstract = "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.",
author = "Charles Lopez and Y. Ao and Rohde, {L. H.} and Perez, {T. D.} and O'Connor, {D. J.} and X. Lu and Ford, {J. M.} and L. Naumovski",
year = "2000",
doi = "10.1128/MCB.20.21.8018-8025.2000",
language = "English (US)",
volume = "20",
pages = "8018--8025",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "21",

}

TY - JOUR

T1 - Proapoptotic p53-interacting protein 53BP2 is induced by UV irradiation but suppressed by p53

AU - Lopez, Charles

AU - Ao, Y.

AU - Rohde, L. H.

AU - Perez, T. D.

AU - O'Connor, D. J.

AU - Lu, X.

AU - Ford, J. M.

AU - Naumovski, L.

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033782188&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033782188&partnerID=8YFLogxK

U2 - 10.1128/MCB.20.21.8018-8025.2000

DO - 10.1128/MCB.20.21.8018-8025.2000

M3 - Article

C2 - 11027272

AN - SCOPUS:0033782188

VL - 20

SP - 8018

EP - 8025

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 21

ER -