The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells
Abstract
Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01-2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/-) mice. The dose response for Trp53+/+ mice showed higher initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.
- Authors:
-
- McMaster Univ., Hamilton, ON (Canada)
- Publication Date:
- Research Org.:
- McMaster Univ., Hamilton, ON (Canada)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1196285
- Grant/Contract Number:
- FG02-07ER64343
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Dose-Response
- Additional Journal Information:
- Journal Volume: 12; Journal Issue: 3; Journal ID: ISSN 1559-3258
- Publisher:
- International Hormesis Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 62 RADIOLOGY AND NUCLEAR MEDICINE; 59 BASIC BIOLOGICAL SCIENCES; Trp53; cell cycle arrest; apoptosis; DNA damage; ionizing radiation
Citation Formats
Lemon, Jennifer A., Taylor, Kristina, Verdecchia, Kyle, Phan, Nghi, and Boreham, Douglas R.. The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells. United States: N. p., 2014.
Web. doi:10.2203/dose-response.14-008.Lemon.
Lemon, Jennifer A., Taylor, Kristina, Verdecchia, Kyle, Phan, Nghi, & Boreham, Douglas R.. The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells. United States. https://doi.org/10.2203/dose-response.14-008.Lemon
Lemon, Jennifer A., Taylor, Kristina, Verdecchia, Kyle, Phan, Nghi, and Boreham, Douglas R.. Wed .
"The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells". United States. https://doi.org/10.2203/dose-response.14-008.Lemon. https://www.osti.gov/servlets/purl/1196285.
@article{osti_1196285,
title = {The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells},
author = {Lemon, Jennifer A. and Taylor, Kristina and Verdecchia, Kyle and Phan, Nghi and Boreham, Douglas R.},
abstractNote = {Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01-2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/-) mice. The dose response for Trp53+/+ mice showed higher initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.},
doi = {10.2203/dose-response.14-008.Lemon},
journal = {Dose-Response},
number = 3,
volume = 12,
place = {United States},
year = {Wed Jan 01 00:00:00 EST 2014},
month = {Wed Jan 01 00:00:00 EST 2014}
}
Web of Science
Works referenced in this record:
Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism
journal, November 2000
- Koury, Mark J.; Price, James O.; Hicks, Geoffrey G.
- Blood, Vol. 96, Issue 9
Comparison of results from mouse bone marrow chromosome aberration and micronucleus tests
journal, January 1995
- Shelby, M. D.; Witt, K. L.
- Environmental and Molecular Mutagenesis, Vol. 25, Issue 4
Links between mutant p53 and genomic instability
journal, January 2012
- Hanel, Walter; Moll, Ute M.
- Journal of Cellular Biochemistry, Vol. 113, Issue 2
The p53 tumor suppressor protein regulates hematopoietic stem cell fate
journal, June 2011
- Asai, Takashi; Liu, Yan; Bae, Narae
- Journal of Cellular Physiology, Vol. 226, Issue 9
Tissue-specific p53 responses to ionizing radiation and their genetic modification: the key to tissue-specific tumour susceptibility?
journal, January 2003
- Coates, Philip J.; Lorimore, Sally A.; Lindsay, Kirsten J.
- The Journal of Pathology, Vol. 201, Issue 3
H2AX in DNA Damage Response
book, January 2011
- Redon, Christophe E.; Dickey, Jennifer S.; Nakamura, Asako J.
- Molecular Determinants of Radiation Response
Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer
journal, December 2012
- Chaabane, Wiem; User, Sırma D.; El-Gazzah, Mohamed
- Archivum Immunologiae et Therapiae Experimentalis, Vol. 61, Issue 1
The role of p53 in tumour suppression: lessons from mouse models
journal, January 1999
- Attardi, L. D.; Jacks, T.
- Cellular and Molecular Life Sciences CMLS, Vol. 55, Issue 1
The use of harlequin staining to measure delay in the human lymphocyte cell cycle induced by in vitro X-irradiation
journal, February 1980
- Purrott, R. J.; Vulpis, N.; Lloyd, D. C.
- Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 69, Issue 2
Kinetics of micronucleus formation in relation to chromosomal aberrations in mouse bone marrow
journal, July 1984
- Hayashi, M.
- Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 127, Issue 2
Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53
journal, September 1992
- Livingstone, Laura R.; White, Alicia; Sprouse, Jason
- Cell, Vol. 70, Issue 6
p53-Dependent apoptosis suppresses tumor growth and progression in vivo
journal, August 1994
- Symonds, Holly; Krall, Leonard; Remington, Lee
- Cell, Vol. 78, Issue 4
p53 accumulation in the organs of low-dose X-ray-irradiated mice
journal, June 1996
- Wang, Xinjiang; Matsumoto, Hideki; Takahashi, Akihisa
- Cancer Letters, Vol. 104, Issue 1
Li-Fraumeni syndrome
journal, January 1994
- Birch, J. M.
- European Journal of Cancer, Vol. 30, Issue 13
The p53 network: p53 and its downstream genes
journal, March 2007
- Shu, Kun-Xian; Li, Biao; Wu, Li-Xiang
- Colloids and Surfaces B: Biointerfaces, Vol. 55, Issue 1
H2AX: the histone guardian of the genome
journal, August 2004
- Fernandez-Capetillo, Oscar; Lee, Alicia; Nussenzweig, Michel
- DNA Repair, Vol. 3, Issue 8-9
Relationship between DNA double-strand break rejoining and cell survival after exposure to ionizing radiation in human fibroblast strains with differing ATM/p53 status: Implications for evaluation of clinical radiosensitivity
journal, December 2006
- Mirzayans, Razmik; Severin, Diane; Murray, David
- International Journal of Radiation Oncology*Biology*Physics, Vol. 66, Issue 5
The role of p53-mediated apoptosis as a crucial anti-tumor response to genomic instability: lessons from mouse models
journal, January 2005
- Attardi, Laura D.
- Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 569, Issue 1-2
Gene expression and apoptosis induction in p53-heterozygous irradiated mice
journal, February 2006
- di Masi, Alessandra; Antoccia, Antonio; Dimauro, Ivan
- Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 594, Issue 1-2
Reticulocyte and micronucleated reticulocyte responses to gamma irradiation: dose–response and time-course profiles measured by flow cytometry
journal, December 2007
- Dertinger, Stephen D.; Tsai, Ying; Nowak, Irena
- Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Vol. 634, Issue 1-2
Reticulocyte and micronucleated reticulocyte responses to gamma irradiation: Effect of age
journal, April 2009
- Dertinger, Stephen D.; Bemis, Jeffrey C.; Phonethepswath, Souk
- Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Vol. 675, Issue 1-2
The p53 network: cellular and systemic DNA damage responses in aging and cancer
journal, March 2012
- Reinhardt, H. Christian; Schumacher, Björn
- Trends in Genetics, Vol. 28, Issue 3
Simple and reliable enumeration of micronucleated reticulocytes with a single-laser flow cytometer
journal, December 1996
- Dertinger, Stephen D.; Torous, Dorothea K.; Tometsko, Kenneth R.
- Mutation Research/Genetic Toxicology, Vol. 371, Issue 3-4
Impact of p53 status on heavy-ion radiation-induced micronuclei in circulating erythrocytes
journal, March 2000
- Chang, Polly Y.; Torous, Dorothea; Lutze-Mann, Louise
- Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Vol. 466, Issue 1
Dissecting p53 tumor suppressor functions in vivo
journal, April 2002
- Schmitt, Clemens A.; Fridman, Jordan S.; Yang, Meng
- Cancer Cell, Vol. 1, Issue 3
p53 is required for radiation-induced apoptosis in mouse thymocytes
journal, April 1993
- Lowe, Scott W.; Schmitt, Earlene M.; Smith, Sallie W.
- Nature, Vol. 362, Issue 6423
Thymocyte apoptosis induced by p53-dependent and independent pathways
journal, April 1993
- Clarke, A. R.; Purdie, C. A.; Harrison, D. J.
- Nature, Vol. 362, Issue 6423
The DNA-damage response in human biology and disease
journal, October 2009
- Jackson, Stephen P.; Bartek, Jiri
- Nature, Vol. 461, Issue 7267
p53 mutations in cancer
journal, January 2013
- Muller, Patricia A. J.; Vousden, Karen H.
- Nature Cell Biology, Vol. 15, Issue 1
p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis
journal, September 1994
- Kemp, Christopher J.; Wheldon, Tom; Balmain, Allan
- Nature Genetics, Vol. 8, Issue 1
Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice
journal, December 2003
- Liu, Geng; Parant, John M.; Lang, Gene
- Nature Genetics, Vol. 36, Issue 1
γH2AX and cancer
journal, November 2008
- Bonner, William M.; Redon, Christophe E.; Dickey, Jennifer S.
- Nature Reviews Cancer, Vol. 8, Issue 12
20 years studying p53 functions in genetically engineered mice
journal, September 2009
- Donehower, Lawrence A.; Lozano, Guillermina
- Nature Reviews Cancer, Vol. 9, Issue 11
Loss of function and p53 protein stabilization
journal, October 1997
- Blagosklonny, Mikhail V.
- Oncogene, Vol. 15, Issue 16
Different impact of p53 and p21 on the radiation response of mouse tissues
journal, July 2000
- Komarova, Elena A.; Christov, Konstantin; Faerman, Alexander I.
- Oncogene, Vol. 19, Issue 33
P53 and radiation responses
journal, August 2003
- Fei, Peiwen; El-Deiry, Wafik S.
- Oncogene, Vol. 22, Issue 37
Control of apoptosis by p53
journal, December 2003
- Fridman, Jordan S.; Lowe, Scott W.
- Oncogene, Vol. 22, Issue 56
Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma.
journal, December 1975
- Knudson, A. G.; Hethcote, H. W.; Brown, B. W.
- Proceedings of the National Academy of Sciences, Vol. 72, Issue 12
DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139
journal, March 1998
- Rogakou, Emmy P.; Pilch, Duane R.; Orr, Ann H.
- Journal of Biological Chemistry, Vol. 273, Issue 10, p. 5858-5868
In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models
journal, January 2010
- Broz, D. K.; Attardi, L. D.
- Carcinogenesis, Vol. 31, Issue 8
Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation
journal, August 1998
- Venkatachalam, S.
- The EMBO Journal, Vol. 17, Issue 16
The complexity of p53 modulation: emerging patterns from divergent signals
journal, October 1998
- Giaccia, A. J.; Kastan, M. B.
- Genes & Development, Vol. 12, Issue 19
p53 mutations in human cancers
journal, July 1991
- Hollstein, M.; Sidransky, D.; Vogelstein, B.
- Science, Vol. 253, Issue 5015
Suppression of human colorectal carcinoma cell growth by wild-type p53
journal, August 1990
- Baker, S.; Markowitz, S.; Fearon, E.
- Science, Vol. 249, Issue 4971
ATM and DNA-PK Function Redundantly to Phosphorylate H2AX after Exposure to Ionizing Radiation
journal, April 2004
- Stiff, Tom; O’Driscoll, Mark; Rief, Nicole
- Cancer Research, Vol. 64, Issue 7
Dose and Dose-rate Effects of X rays and Fission Neutrons on Lymphocyte Apoptosis in p53(+/+) and p53(-/-) Mice
journal, January 2000
- Fujikawa, Kazuo; Hasegawa, Yukinori; Matsuzawa, Shinya
- Journal of Radiation Research, Vol. 41, Issue 2
Micronuclei Induced by Low Dose Rate Irradiation in Early Spermatids of p53 Null and Wild Mice
journal, January 2002
- Kunugita, Naoki; Kakihara, Hiroyo; Kawamoto, Toshihiro
- Journal of Radiation Research, Vol. 43, Issue S
Low Doses of Radiation Increase the Latency of Spontaneous Lymphomas and Spinal Osteosarcomas in Cancer-Prone, Radiation-Sensitive Trp53 Heterozygous Mice
journal, March 2003
- Mitchel, R. E. J.; Jackson, J. S.; Morrison, D. P.
- Radiation Research, Vol. 159, Issue 3
Cancer and Non-cancer Risks in Normal and Cancer-Prone Trp53 Heterozygous Mice Exposed to High-Dose Radiation
journal, January 2010
- Carlisle, S. M.; Burchart, P. A.; Mitchel, R. E. J.
- Radiation Research, Vol. 173, Issue 1
Cell Cycle-Dependent Expression of Phosphorylated Histone H2AX: Reduced Expression in Unirradiated but not X-Irradiated G 1 -Phase Cells
journal, June 2003
- MacPhail, Susan H.; Banáth, Judit P.; Yu, Ying
- Radiation Research, Vol. 159, Issue 6
The Influence of p53 Functions on Radiation-Induced Inflammatory Bystander-Type Signaling in Murine Bone Marrow
journal, April 2013
- Lorimore, Sally A.; Rastogi, Shubhra; Mukherjee, Debayan
- Radiation Research, Vol. 179, Issue 4
The Influence of p53 Functions on Radiation-Induced Inflammatory Bystander-Type Signaling in Murine Bone Marrow
journal, February 2013
- Lorimore, Sally A.; Rastogi, Shubhra; Mukherjee, Debayan
- Radiation Research