{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T07:33:10Z","timestamp":1793431990821,"version":"4.5.0"},"reference-count":24,"publisher":"Radiation Research Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Radiation Research"],"published-print":{"date-parts":[[2022,5,5]]},"abstract":"<jats:p>Thoracic radiation therapy can cause endothelial injury in the heart, leading to cardiac dysfunction and heart failure. Although it has been demonstrated that the tumor suppressor p53 functions in endothelial cells to prevent the development of radiation-induced myocardial injury, the key mechanism(s) by which p53 regulates the radiosensitivity of cardiac endothelial cells is not completely understood. Here, we utilized genetically engineered mice that express mutations in p53 transactivation domain 1 (TAD1) (p5325,26) or mutations in p53 TAD1 and TAD2 (p5325,26,53,54) specifically in endothelial cells to study the p53 transcriptional program that protects cardiac endothelial cells from ionizing radiation in vivo. p5325,26,53,54 loses the ability to drive transactivation of p53 target genes after irradiation while p5325,26 can induce transcription of a group of non-canonical p53 target genes, but not the majority of classic radiation-induced p53 targets critical for p53-mediated cell cycle arrest and apoptosis. After 12 Gy whole-heart irradiation, we found that both p5325,26 and p5325,26,53,54 sensitized mice to radiation-induced cardiac injury, in contrast to wild-type p53. Histopathological examination suggested that mutation of TAD1 contributes to myocardial necrosis after whole-heart irradiation, while mutation of both TAD1 and TAD2 abolishes the ability of p53 to prevent radiation-induced heart disease. Taken together, our results show that the transcriptional program downstream of p53 TAD1, which activates the acute DNA damage response after irradiation, is necessary to protect cardiac endothelial cells from radiation injury in vivo.<\/jats:p>","DOI":"10.1667\/rade-22-00001.1","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T17:04:55Z","timestamp":1651770295000},"page":"145-153","source":"Crossref","is-referenced-by-count":2,"title":["The p53 Transactivation Domain 1-Dependent Response to Acute DNA Damage in Endothelial Cells Protects against Radiation-Induced Cardiac Injury"],"prefix":"10.1667","volume":"198","author":[{"given":"Hsuan-Cheng","family":"Kuo","sequence":"first","affiliation":[{"name":"Departments of Pharmacology and Cancer Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixia","family":"Luo","sequence":"additional","affiliation":[{"name":"Radiation Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ma","sequence":"additional","affiliation":[{"name":"Radiation Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerissa T.","family":"Williams","sequence":"additional","affiliation":[{"name":"Radiation Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"da Silva Campos","sequence":"additional","affiliation":[{"name":"Radiation Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura D.","family":"Attardi","sequence":"additional","affiliation":[{"name":"Division of Radiation and Cancer Biology, Department of Radiation Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Lung","family":"Lee","sequence":"additional","affiliation":[{"name":"Radiation Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Kirsch","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Cancer Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1243","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"J Spetz, J Moslehi, K Sarosiek,  \"Curr Treat Options Cardiovasc Med.\"  20, \"Radiation-induced cardiovascular toxicity: Mechanisms, prevention, and treatment.\" 31 (2018)","DOI":"10.1007\/s11936-018-0627-x"},{"key":"2","doi-asserted-by":"publisher","unstructured":"SC Darby, M Ewertz, P McGale, et al.  \"N Engl J Med.\"  368, \"Risk of ischemic heart disease in women after radiotherapy for breast cancer.\" 987 (2013)","DOI":"10.1056\/NEJMoa1209825"},{"key":"3","doi-asserted-by":"crossref","unstructured":"LE Carlson, GP Watt, ES Tonorezos, et al.  \"JACC CardioOncol.\"  3, \"Coronary Artery disease in young women after radiation therapy for breast cancer: The WECARE study.\" 381 (2021)","DOI":"10.1016\/j.jaccao.2021.07.008"},{"key":"4","doi-asserted-by":"crossref","unstructured":"JE Bates, MH Chen, LS Constine,  \"JACC CardioOncol.\"  3, \"Radiation-associated coronary disease in young cancer survivors: The beat goes on; 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Engeland,  \"Cell Death and Differentiation.\"  25, \"Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM.\" 114 (2018)","DOI":"10.1038\/cdd.2017.172"},{"key":"21","doi-asserted-by":"crossref","unstructured":"JK Nam, AR Kim, SH Choi, et al.  \"Nat Commun.\"  12, \"An antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage.\" 3279 (2021)","DOI":"10.1038\/s41467-021-23478-1"},{"key":"22","doi-asserted-by":"crossref","unstructured":"ME Bowen, J McClendon, HK Long, et al.  \"Dev Cell.\"  50, \"The Spatiotemporal pattern and intensity of p53 Activation dictates phenotypic diversity in p53-driven developmental syndromes.\" 212 (2019)","DOI":"10.1016\/j.devcel.2019.05.015"},{"key":"23","doi-asserted-by":"crossref","unstructured":"D Jiang, EL LaGory, D Kenzelmann Broz, et al.  \"Cell Rep.\"  10, \"Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function.\" 1096 (2015)","DOI":"10.1016\/j.celrep.2015.01.043"},{"key":"24","doi-asserted-by":"publisher","unstructured":"J Schindelin, I Arganda-Carreras, E Frise, et al.  \"Nat Methods.\"  9, \"Fiji: an open-source platform for biological-image analysis.\" 676 (2012)","DOI":"10.1038\/nmeth.2019"},{"key":"6","doi-asserted-by":"crossref","unstructured":"CL Lee, EJ Moding, KC Cuneo, et al.  \"Sci Signal.\"  5, \"p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice.\" ra52 (2012)","DOI":"10.1126\/scisignal.2002918"},{"key":"9","doi-asserted-by":"crossref","unstructured":"SP Jackson  and J Bartek  \"Nature.\"  461, \"The DNA-damage response in human biology and disease.\" 1071 (2009)","DOI":"10.1038\/nature08467"},{"key":"5","doi-asserted-by":"crossref","unstructured":"M Boerma, V Sridharan, XW Mao, et al.  \"Mutat Res Rev Mutat Res.\"  770, \"Effects of ionizing radiation on the heart.\" 319 (2016)","DOI":"10.1016\/j.mrrev.2016.07.003"}],"container-title":["Radiation Research"],"original-title":[],"link":[{"URL":"https:\/\/meridian.allenpress.com\/radiation-research\/article-pdf\/doi\/10.1667\/RADE-22-00001.1\/3054130\/10.1667_rade-22-00001.1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/meridian.allenpress.com\/radiation-research\/article-pdf\/doi\/10.1667\/RADE-22-00001.1\/3054130\/10.1667_rade-22-00001.1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T07:23:53Z","timestamp":1793431433000},"score":1,"resource":{"primary":{"URL":"https:\/\/bioone.org\/journals\/radiation-research\/volume-198\/issue-2\/RADE-22-00001.1\/The-p53-Transactivation-Domain-1-Dependent-Response-to-Acute-DNA\/10.1667\/RADE-22-00001.1.full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,5]]},"references-count":24,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,8,1]]}},"URL":"https:\/\/doi.org\/10.1667\/rade-22-00001.1","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.12.04.471191","asserted-by":"object"}]},"ISSN":["0033-7587","1938-5404"],"issn-type":[{"value":"0033-7587","type":"print"},{"value":"1938-5404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,5]]}}}