Radiation-induced astrocyte senescence is rescued by Δ133p53
Open accessAbstract
BACKGROUND: Cellular senescence and the senescence-associated secretory phenotype (SASP) may contribute to the development of radiation therapy-associated side effects in the lung and blood vessels by promoting chronic inflammation. In the brain, inflammation contributes to the development of neurologic disease, including Alzheimer's disease. In this study, we investigated the roles of cellular senescence and Δ133p53, an inhibitory isoform of p53, in radiation-induced brain injury. METHODS: Senescent cell types in irradiated human brain were identified with immunohistochemical labeling of senescence-associated proteins p16INK4A and heterochromatin protein Hp1γ in 13 patient cases, including 7 irradiated samples. To investigate the impact of radiation on astrocytes specifically, primary human astrocytes were irradiated and examined for expression of Δ133p53 and induction of SASP. Lentiviral expression of ∆133p53 was performed to investigate its role in regulating radiation-induced cellular senescence and astrocyte-mediated neuroinflammation. RESULTS: Astrocytes expressing p16INK4A and Hp1γ were identified in all irradiated tissues, were increased in number in irradiated compared with untreated cancer patient tissues, and had higher labeling intensity in irradiated tissues compared with age-matched controls. Human astrocytes irradiated in vitro also experience induction of cellular senescence, have diminished Δ133p53, and adopt a neurotoxic phenotype as demonstrated by increased senescence-associated beta-galactosidase activity, p16INK4A, and interleukin (IL)-6. In human astrocytes, Δ133p53 inhibits radiation-induced senescence, promotes DNA double-strand break repair, and prevents astrocyte-mediated neuroinflammation and neurotoxicity. CONCLUSIONS: Restoring expression of the endogenous p53 isoform, ∆133p53, protects astrocytes from radiation-induced senescence, promotes DNA repair, and inhibits astrocyte-mediated neuroinflammation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Primary human astrocytes exposed to X-rays exhibit increased expression of senescence-associated proteins (p16INK4a and Hp1γ) and cytokines associated with SASP, such as IL-1β and IL-6.
“Furthermore, primary human astrocytes exposed to X-rays exhibit increased expression of senescence-associated proteins (p16INK4a and Hp1γ) and cytokines associated with SASP, such as IL-1β and IL-6.294–296”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [296]
The Methods (page unavailable) identify primary human astrocytes irradiated with an X-ray irradiator. The Results (page unavailable) report increased p16INK4A, IL-1β, and IL-6 in irradiated astrocytes in vitro. Increased Hp1γ was observed in astrocytes in irradiated patient tissue, but the copy does not report that increase in the primary astrocytes irradiated in vitro. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Aging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954 · see citing works
Cancer and Radiation Therapy: Current Advances and Future Directions
Baskar, R., Lee, K. A., Yeo, R., & Yeoh, K. (2012) · International Journal of Medical Sciences · doi:10.7150/ijms.3635 · Cited by 2,927 · see citing works
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
Inflammatory Blockade Restores Adult Hippocampal Neurogenesis
Monje, M. L., Toda, H., & Palmer, T. D. (2003) · Science · doi:10.1126/science.1088417 · Cited by 2,426 · see citing works
The essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038 · see citing works
Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial.
Patchell, R. A., Tibbs, P. A., Regine, W. F., Dempsey, R. J., Mohiuddin, M., Kryscio, R. J., Markesbery, W. R., Foon, K. A., & Young, B. A. (1998) · PubMed · doi:10.1001/jama.280.17.1485 · Cited by 1,913 · see citing works
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse
Demaria, M., O'Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A. M., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0241 · Cited by 1,338 · see citing works
Irradiation induces neural precursor-cell dysfunction
Monje, M. L., Mizumatsu, S., Fike, J. R., & Palmer, T. D. (2002) · Nature Medicine · doi:10.1038/nm749 · Cited by 1,271 · see citing works
Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · see citing works
Gondi, V., Pugh, S. L., Tomé, W. A., Caine, C., Corn, B. W., Kanner, A. A., Rowley, H. A., Kundapur, V., DeNittis, A. S., Greenspoon, J. N., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.57.2909 · Cited by 1,151 · see citing works
Double-strand break repair: 53BP1 comes into focus
Panier, S., & Boulton, S. J. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3719 · Cited by 1,090 · see citing works
Astrocyte reactivity and reactive astrogliosis: costs and benefits
Pekny, M., & Pekna, M. (2014) · Physiological Reviews · doi:10.1152/physrev.00041.2013 · Cited by 934 · see citing works
Cellular senescence and tumor suppressor gene p16
Rayess, H., Wang, M. B., & Srivatsan, E. S. (2012) · International Journal of Cancer · doi:10.1002/ijc.27316 · Cited by 825 · see citing works
Blum-Degena, D., Müller, T., Kuhn, W., Gerlach, M., Przuntek, H., & Riederer, P. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)12192-7 · Cited by 801 · see citing works
Rola, R., Raber, J., Rizk‐Jackson, A., Otsuka, S., VandenBerg, S. R., Morhardt, D. R., & Fike, J. R. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.05.005 · Cited by 709 · see citing works
Radiation-induced brain injury: A review
Greene-Schloesser, D. M., Robbins, M. E. C., Peiffer, A. M., Shaw, E. G., Wheeler, K. T., & Chan, M. D. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00073 · Cited by 702 · see citing works
Radiation-induced cell death mechanisms
Eriksson, D., & Stigbrand, T. I. (2010) · Tumor Biology · doi:10.1007/s13277-010-0042-8 · Cited by 666 · see citing works
Extreme sensitivity of adult neurogenesis to low doses of X-irradiation.
Mizumatsu, S., Monje, M., Morhardt, D. R., Rola, R., Palmer, T. D., & Fike, J. R. (2003) · PubMed · Cited by 657 · see citing works
Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives
Baker, D. J., & Petersen, R. C. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95145 · Cited by 514 · see citing works
CNS complications of radiotherapy and chemotherapy
Soussain, C., Ricard, D., Fike, J. R., Mazeron, J., Psimaras, D., & Delattre, J. (2009) · The Lancet · doi:10.1016/s0140-6736(09)61299-x · Cited by 407 · see citing works
Wang, C., Ward, M. E., Chen, R., Liu, K., Tracy, T. E., Chen, X., Xie, M., Sohn, P. D., Ludwig, C., Meyer-Franke, A., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.08.019 · Cited by 400 · see citing works
Whole-brain irradiation and decline in intelligence: the influence of dose and age on IQ score.
Silber, J. H., Radcliffe, J., Peckham, V. C., Perilongo, G., Kishnani, P. S., Fridman, M., Goldwein, J. W., & Meadows, A. T. (1992) · Journal of Clinical Oncology · doi:10.1200/jco.1992.10.9.1390 · Cited by 341 · see citing works
p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence
Fujita, K., Mondal, A. M., Horikawa, I., Nguyen, G. H., Kumamoto, K., Sohn, J. J., Bowman, E. D., Mathe, E. A., Schetter, A. J., Pine, S. R., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1928 · Cited by 336 · see citing works
Self-citationSalminen, A., Ojala, J., Kaarniranta, K., Haapasalo, A., Hiltunen, M., & Soininen, H. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07738.x · Cited by 333 · see citing works
Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain
Lumniczky, K., Szatmári, T., & Sáfrány, G. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00517 · Cited by 228 · see citing works
Biological Methods for Cell-Cycle Synchronization of Mammalian Cells
Davis, P. K., Ho, A. L., & Dowdy, S. F. (2001) · BioTechniques · doi:10.2144/01306rv01 · Cited by 211 · see citing works
Neuropsychological performance and quality of life of 10 year survivors of childhood medulloblastoma
Maddrey, A. M., Bergeron, J. A., Lombardo, E. R., McDonald, N., Mulne, A. F., Barenberg, P. D., & Bowers, D. C. (2005) · Journal of Neuro-Oncology · doi:10.1007/s11060-004-3009-z · Cited by 208 · see citing works
Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases
Wang, Y., Boerma, M., & Zhou, D. (2016) · Radiation Research · doi:10.1667/rr14445.1 · Cited by 204 · see citing works
Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain
Lee, W. H., Sonntag, W. E., Mitschelen, M. C., Han, Y., & Lee, Y. W. (2010) · International Journal of Radiation Biology · doi:10.3109/09553000903419346 · Cited by 196 · see citing works
Saatman, K. E., Contreras, P. C., Smith, D. H., Raghupathi, R., McDermott, K. L., Fernandez, S. C., Sanderson, K. L., Voddi, M., & McIntosh, T. K. (1997) · Experimental Neurology · doi:10.1006/exnr.1997.6629 · Cited by 185 · see citing works
Role of Type II Pneumocyte Senescence in Radiation-Induced Lung Fibrosis
Citrin, D. E., Shankavaram, U. T., Horton, J. A., Shield, W. P., Zhao, S., Asano, H., White, A. O., Sowers, A. L., Thetford, A., & Chung, E. J. (2013) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt212 · Cited by 177 · see citing works
p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration
Turnquist, C., Horikawa, I., Foran, E., Major, E. O., Vojtěšek, B., Lane, D. P., Lü, X., Harris, B. T., & Harris, C. C. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2016.37 · Cited by 177 · see citing works
Self-citationCell cycle-dependent expression of the mouseRad51 gene in proliferating cells
Yamamoto, A., Yagi, H., Habu, T., Yoshimura, Y., Matsushiro, A., Nishimune, Y., Morita, T., Taki, T., Yoshida, K., Yamamoto, K., et al. (1996) · Molecular and General Genetics MGG · doi:10.1007/bf02174338 · Cited by 155 · see citing works
Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury
Yang, L., Yang, J., Li, G., Li, Y., Wu, R., Cheng, J., & Tang, Y. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9628-x · Cited by 138 · see citing works
Redmond, K. J., Mahone, E. M., Terezakis, S. A., Ishaq, O. F., Ford, E., McNutt, T., Kleinberg, L. R., Cohen, K. J., Wharam, M. D., & Horská, A. (2013) · Neuro-Oncology · doi:10.1093/neuonc/nos303 · Cited by 131 · see citing works
Marmary, Y., Adar, R., Gaska, S., Wygoda, A., Maly, A., Cohen, J. B., Eliashar, R., Mizrachi, L., Orfaig-Geva, C., Baum, B., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-1671 · Cited by 118 · see citing works
Pathogenesis of Cognitive Decline Following Therapeutic Irradiation for Head and Neck Tumors
Abayomi, O. K. (2002) · Acta Oncologica · doi:10.1080/028418602760169389 · Cited by 116 · see citing works
Changes in the Transcriptome of Human Astrocytes Accompanying Oxidative Stress-Induced Senescence
Crowe, E. P., Tuzer, F., Gregory, B. D., Donahue, G., Gosai, S. J., Cohen, J., Leung, Y. Y., Yetkin, E., Nativio, R., Wang, L.-S., et al. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00208 · Cited by 110 · see citing works
Madathil, S. K., Carlson, S. W., Brelsfoard, J., Ye, P., D’Ercole, A. J., & Saatman, K. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067204 · Cited by 99 · see citing works
Suman, S., Rodriguez, O. C., Winters, T. A., Fornace, A. J., Albanese, C., & Datta, K. (2013) · Aging · doi:10.18632/aging.100587 · Cited by 85 · see citing works
Horikawa, I., Park, K., Isogaya, K., Hiyoshi, Y., Li, H., Anami, K., Robles, A. I., Mondal, A. M., Fujita, K., Serrano, M., et al. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.48 · Cited by 76 · see citing works
Self-citationImmunocytochemical markers of neuronal maturation in human diagnostic neuropathology
Sarnat, H. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1988-4 · Cited by 69 · see citing works
p53 isoforms regulate premature aging in human cells
von Muhlinen, N., Horikawa, I., Alam, F., Isogaya, K., Lissa, D., Vojtesek, B., Lane, D. P., & Harris, C. C. (2018) · Oncogene · doi:10.1038/s41388-017-0101-3 · Cited by 69 · see citing works
Self-citationNeuropathology and the Neuroinflammation Idea
Mrak, R. E. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1158 · Cited by 66 · see citing works
Sohn, J. J., Schetter, A. J., Yfantis, H. G., Ridnour, L. A., Horikawa, I., Ma, K., Robles, A. I., Hussain, S. P., Goto, A., Bowman, E. D., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044156 · Cited by 66 · see citing works
Self-citationImproving Care in Pediatric Neuro-oncology Patients
Fischer, C., Petriccione, M., Donzelli, M. A., & Pottenger, E. M. (2015) · Journal of Child Neurology · doi:10.1177/0883073815597756 · Cited by 61 · see citing works
García‐Matas, S., Cuesta, J., Coto‐Montes, A. M., Rubio‐Acero, R., Díez‐Vives, C., Camins, A., Pallàs, M., Sanfeliu, C., & Cristòfol, R. M. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00410.x · Cited by 56 · see citing works
Dong, X., Luo, M., Huang, G., et al. (2014) · International Journal of Radiation Biology · doi:10.3109/09553002.2014.988895 · Cited by 48 · see citing works
Low-grade gliomas in children: tumor volume response to radiation
Fisher, B. J., Bauman, G. S., Leighton, C. E., Stitt, L., Cairncross, J. G., & Macdonald, D. (1998) · Neurosurgical FOCUS · doi:10.3171/foc.1998.4.4.8 · Cited by 46 · see citing works
Radiation‐induced morphologic changes in the rhesus monkey (Macaca mulatta) brain
Price, R. E., Langford, L. A., Jackson, E. F., et al. (2001) · Journal of Medical Primatology · doi:10.1034/j.1600-0684.2001.300202.x · Cited by 29 · see citing works
TNF, IL-1 and IL-6 in circulating blood after total-body and localized irradiation in rats.
HAVEMAN, J., Geerdink, A. G., & Rodermond, H. M. (1998) · Oncology Reports · doi:10.3892/or.5.3.679 · Cited by 22 · see citing works
Schuitema, I., de Sonneville, L. M. J., Kaspers, G. J. L., van der Pal, H. J. H., Uyttebroeck, A., van den Bos, C., & Veerman, A. J. P. (2015) · Journal of the International Neuropsychological Society · doi:10.1017/s1355617715000788 · Cited by 17 · see citing works
Guillaud, P., Vermont, J., & Seigneurin, D. (1991) · Cell Proliferation · doi:10.1111/j.1365-2184.1991.tb01176.x · Cited by 16 · see citing works
Wang, B., Tanaka, K., Ji, B., Ono, M., Fang, Y., Ninomiya, Y., Maruyama, K., Nakajima, N. I., Begum, N., Higuchi, M., et al. (2014) · Journal of Neuroscience Research · doi:10.1002/jnr.23363 · Cited by 14 · see citing works
Agbahiwe, H. C., Rashid, A., Horská, A., et al. (2016) · Cancer · doi:10.1002/cncr.30313 · Cited by 14 · see citing works
Rowe, L. S., Krauze, A. V., Ning, H., et al. (2017) · PubMed · Cited by 7 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [28]28. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010;24(22):2463–2479. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cited by
Sorted by citations
Inflammation and aging: signaling pathways and intervention therapies
Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443 · see citing works
Role of p53 in the Regulation of Cellular Senescence
Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., & Giordano, A. (2020) · Biomolecules · doi:10.3390/biom10030420 · Cited by 639 · see citing works
SenNet recommendations for detecting senescent cells in different tissues
Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., et al. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00738-8 · Cited by 408 · see citing works
“…radiation) and metabolic and inflammatory stress (including obesity and alcoholism) recapitulate features of age-associated and disease-associated senescence in the mouse brain, as characterized by the induction of CDKN2A, CDKN2D, CDKN1A, p53, IL-1α, IL-1β, IL-6 and SA-β-gal activity 102,117,118 .”
Fletcher-Sananikone, E., Kanji, S., Tomimatsu, N., Di Cristofaro, L. F. M., Kollipara, R. K., Saha, D., Floyd, J. R., Sung, P., Hromas, R., Burns, T. C., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0752 · Cited by 212 · see citing works
Kiss, T., Nyúl-Tóth, Á., Balasubramanian, P., Tarantini, S., Ahire, C., DelFavero, J., Yabluchanskiy, A., Csipo, T., Farkas, E., Wiley, G., et al. (2020) · GeroScience · doi:10.1007/s11357-020-00177-1 · Cited by 203 · see citing works
Matias, I., Diniz, L. P., Damico, I. V., Araujo, A. P. B., Neves, L. D. S., Vargas, G., Leite, R. E. P., Suemoto, C. K., Nitrini, R., Jacob‐Filho, W., et al. (2022) · Aging Cell · doi:10.1111/acel.13521 · Cited by 183 · see citing works
Astrocyte Senescence and Alzheimer’s Disease: A Review
Han, X., Zhang, T., Liu, H., Mi, Y., & Gou, X. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00148 · Cited by 177 · see citing works
- Authors
- Turnquist, C., Beck, J. A., Horikawa, I., Obiorah, I. E., Von Muhlinen, N., Vojtesek, B., Lane, D. P., Grunseich, C., Chahine, J. J., Ames, H. M., Smart, D. D., Harris, B. T., & Harris, C. C.
- Affiliations
- National Institutes of Health (US)
- Georgetown University Medical Center (US)
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
- Agency for Science, Technology and Research (SG)
- University of Maryland, Baltimore (US)
- Corresponding author
- Harris, Brent T
- Harris, Curtis C
- ORCID
- Venue
- Neuro-Oncology
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-01-04
- Volume
- 21
- Issue
- 4
- Pages
- 474-485
- ISSN
- 1522-8517 (ISSN-L)
- 1523-5866
- PMC
- PMC6422440
- OpenAlex
- W2906978840
- Cited by
- 118
- References
- 56
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 23 · 2023: 17 · 2022: 12 · 2021: 19 · 2020: 19 · 2019: 2
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuro-Oncology (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Regional development fund
- Czech Science Foundation (P206/12/G151)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- radiation-induced senescence, astrocytes, Δ133p53, p53 isoforms, senescence-associated secretory phenotype, neuroinflammation, radiation-induced brain injury, p16INK4a, DNA double-strand break repair, interleukin-6, neurotoxicity, radiotherapy complications
- MeSH terms
- Astrocytes, Brain Neoplasms, Cells, Cultured, Humans, Radiation Injuries, Tumor Suppressor Protein p53, Cranial Irradiation, Cellular Senescence, Protein Isoforms
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
