{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:32:58Z","timestamp":1790667178247,"version":"4.1.0"},"reference-count":183,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T00:00:00Z","timestamp":1733011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["32471260"],"award-info":[{"award-number":["32471260"]}]},{"name":"National Natural Science Foundation of China","award":["2024D01C266"],"award-info":[{"award-number":["2024D01C266"]}]},{"name":"National Natural Science Foundation of China","award":["2023TSYCLJ0043"],"award-info":[{"award-number":["2023TSYCLJ0043"]}]},{"name":"National Natural Science Foundation of China","award":["XJEDU2023P017"],"award-info":[{"award-number":["XJEDU2023P017"]}]},{"name":"National Natural Science Foundation of China","award":["2023B02030-1"],"award-info":[{"award-number":["2023B02030-1"]}]},{"name":"National Natural Science Foundation of China","award":["2023B02030-2"],"award-info":[{"award-number":["2023B02030-2"]}]},{"name":"National Natural Science Foundation of China","award":["2023B02030-3"],"award-info":[{"award-number":["2023B02030-3"]}]},{"name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","award":["32471260"],"award-info":[{"award-number":["32471260"]}]},{"name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","award":["2024D01C266"],"award-info":[{"award-number":["2024D01C266"]}]},{"name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","award":["2023TSYCLJ0043"],"award-info":[{"award-number":["2023TSYCLJ0043"]}]},{"name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","award":["XJEDU2023P017"],"award-info":[{"award-number":["XJEDU2023P017"]}]},{"name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","award":["2023B02030-1"],"award-info":[{"award-number":["2023B02030-1"]}]},{"name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","award":["2023B02030-2"],"award-info":[{"award-number":["2023B02030-2"]}]},{"name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","award":["2023B02030-3"],"award-info":[{"award-number":["2023B02030-3"]}]},{"name":"Tianshan Talent Training Program","award":["32471260"],"award-info":[{"award-number":["32471260"]}]},{"name":"Tianshan Talent Training Program","award":["2024D01C266"],"award-info":[{"award-number":["2024D01C266"]}]},{"name":"Tianshan Talent Training Program","award":["2023TSYCLJ0043"],"award-info":[{"award-number":["2023TSYCLJ0043"]}]},{"name":"Tianshan Talent Training Program","award":["XJEDU2023P017"],"award-info":[{"award-number":["XJEDU2023P017"]}]},{"name":"Tianshan Talent Training Program","award":["2023B02030-1"],"award-info":[{"award-number":["2023B02030-1"]}]},{"name":"Tianshan Talent Training Program","award":["2023B02030-2"],"award-info":[{"award-number":["2023B02030-2"]}]},{"name":"Tianshan Talent Training Program","award":["2023B02030-3"],"award-info":[{"award-number":["2023B02030-3"]}]},{"name":"Autonomous Region Universities Basic Research Funds Research Projects-Cultivation Projects","award":["32471260"],"award-info":[{"award-number":["32471260"]}]},{"name":"Autonomous Region Universities Basic Research Funds Research Projects-Cultivation Projects","award":["2024D01C266"],"award-info":[{"award-number":["2024D01C266"]}]},{"name":"Autonomous Region Universities Basic Research Funds Research Projects-Cultivation Projects","award":["2023TSYCLJ0043"],"award-info":[{"award-number":["2023TSYCLJ0043"]}]},{"name":"Autonomous Region Universities Basic Research Funds Research Projects-Cultivation Projects","award":["XJEDU2023P017"],"award-info":[{"award-number":["XJEDU2023P017"]}]},{"name":"Autonomous Region Universities Basic Research Funds Research Projects-Cultivation Projects","award":["2023B02030-1"],"award-info":[{"award-number":["2023B02030-1"]}]},{"name":"Autonomous Region Universities Basic Research Funds Research Projects-Cultivation Projects","award":["2023B02030-2"],"award-info":[{"award-number":["2023B02030-2"]}]},{"name":"Autonomous Region Universities Basic Research Funds Research Projects-Cultivation Projects","award":["2023B02030-3"],"award-info":[{"award-number":["2023B02030-3"]}]},{"name":"Key Research and Development Program in the Xinjiang Uygur Autonomous Region","award":["32471260"],"award-info":[{"award-number":["32471260"]}]},{"name":"Key Research and Development Program in the Xinjiang Uygur Autonomous Region","award":["2024D01C266"],"award-info":[{"award-number":["2024D01C266"]}]},{"name":"Key Research and Development Program in the Xinjiang Uygur Autonomous Region","award":["2023TSYCLJ0043"],"award-info":[{"award-number":["2023TSYCLJ0043"]}]},{"name":"Key Research and Development Program in the Xinjiang Uygur Autonomous Region","award":["XJEDU2023P017"],"award-info":[{"award-number":["XJEDU2023P017"]}]},{"name":"Key Research and Development Program in the Xinjiang Uygur Autonomous Region","award":["2023B02030-1"],"award-info":[{"award-number":["2023B02030-1"]}]},{"name":"Key Research and Development Program in the Xinjiang Uygur Autonomous Region","award":["2023B02030-2"],"award-info":[{"award-number":["2023B02030-2"]}]},{"name":"Key Research and Development Program in the Xinjiang Uygur Autonomous Region","award":["2023B02030-3"],"award-info":[{"award-number":["2023B02030-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>DNA damage can lead to mutations that can alter the function of oncogenes or tumor suppressor genes, thus promoting the development of cancer. p53 plays a multifaceted and complex role in the DNA damage response and cancer progression and is known as the \u2018guardian of the gene\u2019. When DNA damage occurs, p53 is activated through a series of post-translational modifications, which stabilize the protein and enhance its function as a transcription factor. It regulates processes including cell cycle checkpoints, DNA repair and apoptosis, thereby preventing the spread of damaged DNA and maintaining genome integrity. On the one hand, p53 can initiate cell cycle arrest and induce cells to enter the G1\/S and G2\/M checkpoints, preventing cells with damaged DNA from continuing to proliferate and gaining time for DNA repair. At the same time, p53 can promote the activation of DNA repair pathways, including base excision repair, nucleotide excision repair and other repair pathways, to ensure the integrity of genetic material. If the damage is too severe to repair, p53 will trigger the apoptosis process to eliminate potential cancer risks in time. p53 also plays a pivotal role in cancer progression. Mutations in the p53 gene are frequently found in many cancers, and the mutated p53 not only loses its normal tumor suppressor function but may even acquire pro-cancer activity. Therefore, we also discuss therapeutic strategies targeting the p53 pathway, such as the use of small-molecule drugs to restore the function of wild-type p53, the inhibition of negative regulatory factors and synthetic lethality approaches for p53-deficient tumors. This review therefore highlights the important role of p53 in maintaining genomic stability and its potential in therapeutic strategies for cancer.<\/jats:p>","DOI":"10.3390\/ijms252312928","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T05:43:43Z","timestamp":1733118223000},"page":"12928","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Unraveling the Guardian: p53\u2019s Multifaceted Role in the DNA Damage Response and Tumor Treatment Strategies"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1955-9687","authenticated-orcid":false,"given":"Han","family":"Zhang","sequence":"first","affiliation":[{"name":"Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxiong","family":"Xu","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7555-0738","authenticated-orcid":false,"given":"Yuxuan","family":"Long","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayitila","family":"Maimaitijiang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3558-001X","authenticated-orcid":false,"given":"Zhengding","family":"Su","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0436-4277","authenticated-orcid":false,"given":"Wenfang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-6096","authenticated-orcid":false,"given":"Jinyao","family":"Li","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1146\/annurev.pharmtox.41.1.367","article-title":"Cellular Responses to DNA Damage","volume":"41","author":"Norbury","year":"2001","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41571-018-0114-z","article-title":"State-of-the-art strategies for targeting the DNA damage response in cancer","volume":"16","author":"Tang","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12491","DOI":"10.1074\/jbc.C200093200","article-title":"ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation","volume":"277","author":"Saito","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1101\/gad.14.3.289","article-title":"The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites","volume":"14","author":"Shieh","year":"2000","journal-title":"Genes Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/358015a0","article-title":"p53, guardian of the genome","volume":"358","author":"Lane","year":"1992","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0092-8674(79)90293-9","article-title":"Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells","volume":"17","author":"Linzer","year":"1979","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nrc2716","article-title":"Tumour suppression by p53: A role for the DNA damage response?","volume":"9","author":"Meek","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/j.ccell.2024.04.009","article-title":"Understanding the complexity of p53 in a new era of tumor suppression","volume":"42","author":"Liu","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1093\/jmcb\/mjz060","article-title":"p53 modifications: Exquisite decorations of the powerful guardian","volume":"11","author":"Liu","year":"2019","journal-title":"J. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ceb.2009.12.001","article-title":"Autophagy regulation by p53","volume":"22","author":"Maiuri","year":"2010","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.molmet.2019.10.002","article-title":"Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer","volume":"33","author":"Lacroix","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/j.cell.2024.02.043","article-title":"p53: A tale of complexity and context","volume":"187","author":"Oren","year":"2024","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"216766","DOI":"10.1016\/j.canlet.2024.216766","article-title":"Potential role of p53 deregulation in modulating immune responses in human malignancies: A paradigm to develop immunotherapy","volume":"588","author":"Chauhan","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1158\/0008-5472.CAN-16-2832","article-title":"Local Activation of p53 in the Tumor Microenvironment Overcomes Immune Suppression and Enhances Antitumor Immunity","volume":"77","author":"Guo","year":"2017","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wang, X., Yang, J., Yang, W., Sheng, H., Jia, B., Cheng, P., Xu, S., Hong, X., Jiang, C., and Yang, Y. Multiple roles of p53 in cancer development: Regulation of tumor microenvironment, m6A modification and diverse cell death mechanisms. J. Adv. Res., 2024. in press.","DOI":"10.1016\/j.jare.2024.10.026"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature12634","article-title":"Mutational landscape and significance across 12 major cancer types","volume":"502","author":"Kandoth","year":"2013","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1097\/CCO.0b013e3283412dfa","article-title":"Somatic mutations in cancer prognosis and prediction: Lessons from TP53 and EGFR genes","volume":"23","author":"Olivier","year":"2011","journal-title":"Curr. Opin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1126\/science.aay4319","article-title":"How to lose tumor suppression","volume":"365","author":"Lane","year":"2019","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zawacka-Pankau, J.E. (2020). The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing. Cancers, 12.","DOI":"10.20944\/preprints202008.0729.v1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-230X(06)97001-8","article-title":"Structural Biology of the Tumor Suppressor p53 and Cancer-Associated Mutants","volume":"Volume 97","author":"Joerger","year":"2007","journal-title":"Advances in Cancer Research"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.molcel.2006.05.015","article-title":"Structural Basis of DNA Recognition by p53 Tetramers","volume":"22","author":"Kitayner","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3342","DOI":"10.1093\/emboj\/17.12.3342","article-title":"How p53 binds DNA as a tetramer","volume":"17","author":"McLure","year":"1998","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1126\/science.274.5289.948","article-title":"Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain","volume":"274","author":"Kussie","year":"1996","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1126\/science.8023157","article-title":"Crystal structure of a p53 tumor suppressor-DNA complex: Understanding tumorigenic mutations","volume":"265","author":"Cho","year":"1994","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1002\/prot.21854","article-title":"Solvent-exposed residues located in the beta-sheet modulate the stability of the tetramerization domain of p53--a structural and combinatorial approach","volume":"71","author":"Mora","year":"2008","journal-title":"Proteins"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/0092-8674(92)90644-R","article-title":"The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation","volume":"69","author":"Momand","year":"1992","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/387296a0","article-title":"Mdm2 promotes the rapid degradation of p53","volume":"387","author":"Haupt","year":"1997","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1126\/science.1091362","article-title":"Mono- versus polyubiquitination: Differential control of p53 fate by Mdm2","volume":"302","author":"Li","year":"2003","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1146\/annurev-pathol-012414-040349","article-title":"The Roles of MDM2 and MDMX in Cancer","volume":"11","author":"Lokshin","year":"2016","journal-title":"Annu. Rev. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/onc.2009.71","article-title":"Regulation by phosphorylation of the relative affinities of the N-terminal transactivation domains of p53 for p300 domains and Mdm2","volume":"28","author":"Teufel","year":"2009","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.molcel.2013.10.031","article-title":"Phosphorylation of p53 by TAF1 inactivates p53-dependent transcription in the DNA damage response","volume":"53","author":"Wu","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/S0092-8674(00)80521-8","article-title":"Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain","volume":"90","author":"Gu","year":"1997","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/nature19759","article-title":"Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode","volume":"538","author":"Wang","year":"2016","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.cell.2008.03.025","article-title":"Acetylation is indispensable for p53 activation","volume":"133","author":"Tang","year":"2008","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1038\/ncb1802","article-title":"Arginine methylation regulates the p53 response","volume":"10","author":"Jansson","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.molcel.2007.07.012","article-title":"Modulation of p53 function by SET8-mediated methylation at lysine 382","volume":"27","author":"Shi","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nature05287","article-title":"Repression of p53 activity by Smyd2-mediated methylation","volume":"444","author":"Huang","year":"2006","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1016\/j.cell.2024.04.002","article-title":"Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis","volume":"187","author":"Zong","year":"2024","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1038\/sj.onc.1205169","article-title":"PARP-1 modifies the effectiveness of p53-mediated DNA damage response","volume":"21","author":"Valenzuela","year":"2002","journal-title":"Oncogene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1038\/ncb1470","article-title":"Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability","volume":"8","author":"Yang","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1126\/science.1092472","article-title":"In vivo activation of the p53 pathway by small-molecule antagonists of MDM2","volume":"303","author":"Vassilev","year":"2004","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.celrep.2018.06.108","article-title":"PHD3 Regulates p53 Protein Stability by Hydroxylating Proline 359","volume":"24","author":"Rodriguez","year":"2018","journal-title":"Cell Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/s41419-019-1463-y","article-title":"p53 \u03b2-hydroxybutyrylation attenuates p53 activity","volume":"10","author":"Liu","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10764","DOI":"10.1073\/pnas.96.19.10764","article-title":"Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents","volume":"96","author":"Hickman","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.cell.2009.04.037","article-title":"Blinded by the Light: The Growing Complexity of p53","volume":"137","author":"Vousden","year":"2009","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"37536","DOI":"10.1074\/jbc.M305135200","article-title":"Phosphorylation site interdependence of human p53 post-translational modifications in response to stress","volume":"278","author":"Saito","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"33048","DOI":"10.1074\/jbc.273.49.33048","article-title":"Phosphorylation of p53 serine 15 increases interaction with CBP","volume":"273","author":"Lambert","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15579","DOI":"10.1074\/jbc.M106915200","article-title":"Effect of phosphorylation on the structure and fold of transactivation domain of p53","volume":"277","author":"Kar","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1101\/gad.12.18.2831","article-title":"DNA damage activates p53 through a phosphorylation-acetylation cascade","volume":"12","author":"Sakaguchi","year":"1998","journal-title":"Genes Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1038\/s12276-022-00863-4","article-title":"DNA damage response revisited: The p53 family and its regulators provide endless cancer therapy opportunities","volume":"54","author":"Abuetabh","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.dnarep.2009.04.006","article-title":"Common mechanisms of PIKK regulation","volume":"8","author":"Lovejoy","year":"2009","journal-title":"DNA Repair"},{"key":"ref_52","first-page":"1689","article-title":"UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells","volume":"4","author":"Maltzman","year":"1984","journal-title":"Mol. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s000180050271","article-title":"Covalent and noncovalent modifiers of the p53 protein","volume":"55","author":"Jayaraman","year":"1999","journal-title":"Cell Mol. Life Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nsb0901-730","article-title":"The C-terminus of p53: The more you learn the less you know","volume":"8","author":"Ahn","year":"2001","journal-title":"Nat. Struct. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1158\/1078-0432.CCR-09-1029","article-title":"New Insights into Checkpoint Kinase 1 in the DNA Damage Response Signaling Network","volume":"16","author":"Dai","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41580-021-00404-3","article-title":"Cell cycle control in cancer","volume":"23","author":"Matthews","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1017\/erm.2020.3","article-title":"DNA damage checkpoint kinases in cancer","volume":"22","author":"Smith","year":"2020","journal-title":"Expert. Rev. Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature03097","article-title":"Cell-cycle checkpoints and cancer","volume":"432","author":"Kastan","year":"2004","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1126\/science.282.5393.1497","article-title":"Requirement for p53 and p21 to sustain G2 arrest after DNA damage","volume":"282","author":"Bunz","year":"1998","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/embor.2013.25","article-title":"Another fork in the road\u2014Life or death decisions by the tumour suppressor p53","volume":"14","author":"Carvajal","year":"2013","journal-title":"EMBO Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/s41418-022-00988-z","article-title":"Cell cycle regulation: p53-p21-RB signaling","volume":"29","author":"Engeland","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nrc2723","article-title":"The first 30 years of p53: Growing ever more complex","volume":"9","author":"Levine","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/S0955-0674(00)00280-5","article-title":"Mammalian G1- and S-phase checkpoints in response to DNA damage","volume":"13","author":"Bartek","year":"2001","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/cdd.2017.172","article-title":"Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM","volume":"25","author":"Engeland","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1038\/sj.onc.1204252","article-title":"Regulation of the G2\/M transition by p53","volume":"20","author":"Taylor","year":"2001","journal-title":"Oncogene"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"22627","DOI":"10.1074\/jbc.C000235200","article-title":"Reprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phase","volume":"275","author":"Ohki","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_67","first-page":"1819","article-title":"Effect of UV-irradiation on cell cycle, viability and the expression of p53, gadd153 and gadd45 genes in normal and HPV-immortalized human oral keratinocytes","volume":"9","author":"Gujuluva","year":"1994","journal-title":"Oncogene"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1101\/gad.343186.120","article-title":"p53 directly represses human LINE1 transposons","volume":"34","author":"Tiwari","year":"2020","journal-title":"Genes Dev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"a026070","DOI":"10.1101\/cshperspect.a026070","article-title":"p53 in the DNA-Damage-Repair Process","volume":"6","author":"Williams","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.tcb.2007.04.004","article-title":"p53: New roles in metabolism","volume":"17","author":"Bensaad","year":"2007","journal-title":"Trends Cell Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1093\/carcin\/bgg031","article-title":"p53 responsive nucleotide excision repair gene products p48 and XPC, but not p53, localize to sites of UV-irradiation-induced DNA damage, in vivo","volume":"24","author":"Fitch","year":"2003","journal-title":"Carcinogenesis"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/ng0695-188","article-title":"p53 modulation of TFIIH\u2013associated nucleotide excision repair activity","volume":"10","author":"Wang","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1093\/emboj\/cdg082","article-title":"p53 is a chromatin accessibility factor for nucleotide excision repair of DNA damage","volume":"22","author":"Rubbi","year":"2003","journal-title":"EMBO J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0022-1910(65)90099-5","article-title":"Programmed Cell Death--I. Cytology of Degeneration in the Intersegmental muscles of the Pernyi silkmoth","volume":"11","author":"Lockshin","year":"1965","journal-title":"J. Insect Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.cell.2011.10.033","article-title":"Programmed cell death in animal development and disease","volume":"147","author":"Fuchs","year":"2011","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1126\/science.1092734","article-title":"Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis","volume":"303","author":"Chipuk","year":"2004","journal-title":"Science"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/s41419-021-03902-6","article-title":"Puma, noxa, p53, and p63 differentially mediate stress pathway induced apoptosis","volume":"12","author":"Wang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1126\/science.282.5387.290","article-title":"Cell Surface Trafficking of Fas: A Rapid Mechanism of p53-Mediated Apoptosis","volume":"282","author":"Bennett","year":"1998","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","article-title":"Hallmarks of Cellular Senescence","volume":"28","author":"Nehme","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/S1097-2765(04)00256-4","article-title":"Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a)","volume":"14","author":"Herbig","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0092-8674(01)00504-9","article-title":"The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability","volume":"107","author":"Hemann","year":"2001","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/S0959-437X(00)00163-5","article-title":"Cellular senescence as a tumor-protection mechanism: The essential role of counting","volume":"11","author":"Wright","year":"2001","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1172\/JCI200420663","article-title":"When cells get stressed: An integrative view of cellular senescence","volume":"113","author":"Weinberg","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/35036093","article-title":"Hayflick, his limit, and cellular ageing","volume":"1","author":"Shay","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1101\/gad.235184.113","article-title":"Cellular senescence and its effector programs","volume":"28","author":"Salama","year":"2014","journal-title":"Genes Dev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S0092-8674(00)81902-9","article-title":"Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a","volume":"88","author":"Serrano","year":"1997","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nature02118","article-title":"A DNA damage checkpoint response in telomere-initiated senescence","volume":"426","author":"Fagagna","year":"2003","journal-title":"Nature"},{"key":"ref_88","first-page":"2853","article-title":"Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor","volume":"6","author":"Patil","year":"2008","journal-title":"PLoS Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/nm.4000","article-title":"Cellular senescence in aging and age-related disease: From mechanisms to therapy","volume":"21","author":"Childs","year":"2015","journal-title":"Nat. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nature11861","article-title":"mTOR is a key modulator of ageing and age-related disease","volume":"493","author":"Johnson","year":"2013","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.cmet.2016.05.010","article-title":"From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence","volume":"23","author":"Wiley","year":"2016","journal-title":"Cell Metab."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/345458a0","article-title":"Telomeres shorten during ageing of human fibroblasts","volume":"345","author":"Harley","year":"1990","journal-title":"Nature"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1172\/JCI95148","article-title":"Mechanisms and functions of cellular senescence","volume":"128","author":"Herranz","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1101\/gad.1971610","article-title":"The essence of senescence","volume":"24","author":"Kuilman","year":"2010","journal-title":"Genes Dev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1093\/emboj\/cdg417","article-title":"Reversal of human cellular senescence: Roles of the p53 and p16 pathways","volume":"22","author":"Krtolica","year":"2003","journal-title":"EMBO J."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., and Giordano, A. (2020). Role of p53 in the Regulation of Cellular Senescence. Biomolecules, 10.","DOI":"10.3390\/biom10030420"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3456","DOI":"10.1038\/onc.2009.222","article-title":"Rb2\/p130 is the dominating pocket protein in the p53-p21 DNA damage response pathway leading to senescence","volume":"28","author":"Helmbold","year":"2009","journal-title":"Oncogene"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Carotenuto, F., Albertini, M.C., Coletti, D., Vilmercati, A., Campanella, L., Darzynkiewicz, Z., and Teodori, L. (2016). How Diet Intervention via Modulation of DNA Damage Response through MicroRNAs May Have an Effect on Cancer Prevention and Aging, an in Silico Study. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050752"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1101\/gad.625811","article-title":"Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS)","volume":"25","author":"Ohanna","year":"2011","journal-title":"Genes Dev."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"14995","DOI":"10.1038\/ncomms14995","article-title":"Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression","volume":"8","author":"Contrepois","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"808","DOI":"10.4161\/auto.23922","article-title":"Autophagy and senescence: A partnership in search of definition","volume":"9","author":"Gewirtz","year":"2013","journal-title":"Autophagy"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.cell.2006.05.036","article-title":"TIGAR, a p53-inducible regulator of glycolysis and apoptosis","volume":"126","author":"Bensaad","year":"2006","journal-title":"Cell"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/cdd.2017.180","article-title":"Why are there hotspot mutations in the TP53 gene in human cancers?","volume":"25","author":"Baugh","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1016\/j.celrep.2019.07.001","article-title":"Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas","volume":"28","author":"Donehower","year":"2019","journal-title":"Cell Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"a026179","DOI":"10.1101\/cshperspect.a026179","article-title":"Somatic TP53 Mutations in the Era of Genome Sequencing","volume":"6","author":"Hainaut","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41418-018-0246-9","article-title":"Mutant p53 as a guardian of the cancer cell","volume":"26","author":"Mantovani","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1177\/1947601911408889","article-title":"Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis","volume":"2","author":"Rivlin","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/cdd.2017.185","article-title":"Mutant p53 partners in crime","volume":"25","author":"Kim","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nature22312","article-title":"Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations","volume":"545","author":"Merkle","year":"2017","journal-title":"Nature"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"188","DOI":"10.15252\/embr.201540488","article-title":"YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins","volume":"17","author":"Sorrentino","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1038\/sj.onc.1210312","article-title":"Interactions of mutant p53 with DNA: Guilt by association","volume":"26","author":"Kim","year":"2007","journal-title":"Oncogene"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"13681","DOI":"10.1073\/pnas.95.23.13681","article-title":"Specific interaction of mutant p53 with regions of matrix attachment region DNA elements (MARs) with a high potential for base-unpairing","volume":"95","author":"Will","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nature15251","article-title":"Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth","volume":"525","author":"Zhu","year":"2015","journal-title":"Nature"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.molonc.2016.05.007","article-title":"A rare DNA contact mutation in cancer confers p53 gain-of-function and tumor cell survival via TNFAIP8 induction","volume":"10","author":"Monteith","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.drup.2018.05.001","article-title":"How Mutations Shape P53 Interactions with the Genome to Promote Tumorigenesis and Drug Resistance","volume":"38","author":"Stiewe","year":"2018","journal-title":"Drug Resist. Updates"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.molcel.2020.08.021","article-title":"Gut Microbes\u2019 Impact on Oncogenic Drivers: Location Matters","volume":"79","author":"White","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/ncb3380","article-title":"Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer","volume":"18","author":"Walerych","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/BF01535205","article-title":"Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line","volume":"13","author":"Francke","year":"1987","journal-title":"Somat. Cell Mol. Genet."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1002\/j.1460-2075.1991.tb07676.x","article-title":"Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line","volume":"10","author":"Fakharzadeh","year":"1991","journal-title":"EMBO J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"eaay2163","DOI":"10.1126\/scitranslmed.aay2163","article-title":"Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma","volume":"12","author":"Pyrdziak","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3453","DOI":"10.1093\/nar\/26.15.3453","article-title":"The MDM2 gene amplification database","volume":"26","author":"Momand","year":"1998","journal-title":"Nucleic Acids Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1746-1596-9-71","article-title":"Amplification of Mdmx and overexpression of MDM2 contribute to mammary carcinogenesis by substituting for p53 mutations","volume":"9","author":"Yu","year":"2014","journal-title":"Diagn. Pathol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"5835","DOI":"10.1128\/MCB.24.13.5835-5843.2004","article-title":"Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity","volume":"24","author":"Danovi","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.ebiom.2019.08.070","article-title":"Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitination","volume":"48","author":"Huang","year":"2019","journal-title":"eBioMedicine"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Zhou, T., Ke, Z., Ma, Q., Xiang, J., Gao, M., Huang, Y., Cheng, X., and Su, Z. (2023). Molecular mechanism of CCDC106 regulating the p53-Mdm2\/MdmX signaling axis. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-47808-z"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1038\/s41401-020-00599-9","article-title":"The transcription factor PBX3 promotes tumor cell growth through transcriptional suppression of the tumor suppressor p53","volume":"42","author":"Li","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/cas.14233","article-title":"Neurogenic differentiation factor 1 promotes colorectal cancer cell proliferation and tumorigenesis by suppressing the p53\/p21 axis","volume":"111","author":"Lei","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Qi, S.-M., Cheng, G., Cheng, X.-D., Xu, Z., Xu, B., Zhang, W.-D., and Qin, J.-J. (2020). Targeting USP7-Mediated Deubiquitination of MDM2\/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00233"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/sj.cdd.4402309","article-title":"Structure of the MDM2\/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans","volume":"15","author":"Linke","year":"2008","journal-title":"Cell Death Differ."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1158\/0008-5472.CAN-21-2709","article-title":"Targeting the P53 Protein for Cancer Therapies: The Translational Impact of P53 Research","volume":"82","author":"Levine","year":"2022","journal-title":"Cancer Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s41573-022-00571-8","article-title":"Drugging p53 in cancer: One protein, many targets","volume":"22","author":"Hassin","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/nm0302-282","article-title":"Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound","volume":"8","author":"Bykov","year":"2002","journal-title":"Nat. Med."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1038\/s41416-022-01971-8","article-title":"Mutant p53 gain of function mediates cancer immune escape that is counteracted by APR-246","volume":"127","author":"Zhou","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"e202301999","DOI":"10.26508\/lsa.202301999","article-title":"APR-246 increases tumor antigenicity independent of p53","volume":"7","author":"Michels","year":"2024","journal-title":"Life Sci. Alliance"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"60724","DOI":"10.18632\/oncotarget.20600","article-title":"Correction: COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo","volume":"8","author":"Salim","year":"2017","journal-title":"Oncotarget"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1186\/s13046-019-1267-z","article-title":"p53 mutant-type in human prostate cancer cells determines the sensitivity to phenethyl isothiocyanate induced growth inhibition","volume":"38","author":"Aggarwal","year":"2019","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Xiao, J., Zhou, N., Li, Y., Xiao, Y., Chen, W., Ye, J., Ma, T., and Zhang, Y. (2020). PEITC inhibits the invasion and migration of colorectal cancer cells by blocking TGF-\u03b2-induced EMT. Biomed. Pharmacother., 130.","DOI":"10.1016\/j.biopha.2020.110743"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/s41401-020-0376-8","article-title":"PEITC triggers multiple forms of cell death by GSH-iron-ROS regulation in K7M2 murine osteosarcoma cells","volume":"41","author":"Lv","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1182\/blood-2023-181186","article-title":"Selective Targeting of TP53-Y220C Mutant AML By PC14586 Results in TP53 Wild-Type Conformation and Synergistical Apoptosis Induction By Concomitant Inhibition of Xpo-1, MDM2, or Bcl-2","volume":"142","author":"Carter","year":"2023","journal-title":"Blood"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1126\/science.1183424","article-title":"Arsenic Trioxide Controls the Fate of the PML-RAR\u03b1 Oncoprotein by Directly Binding PML","volume":"328","author":"Zhang","year":"2010","journal-title":"Science"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ccell.2020.11.013","article-title":"Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site","volume":"39","author":"Chen","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1038\/s41467-018-03599-w","article-title":"USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells","volume":"9","author":"Padmanabhan","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1038\/cdd.2011.71","article-title":"SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis","volume":"18","author":"Li","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Nishikawa, S., and Iwakuma, T. (2023). Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials. Cancers, 15.","DOI":"10.3390\/cancers15020429"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Zhang, S., Carlsen, L., Hernandez Borrero, L., Seyhan, A.A., Tian, X., and El-Deiry, W.S. (2022). Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer. Biomolecules, 12.","DOI":"10.20944\/preprints202201.0020.v1"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"5029","DOI":"10.1182\/blood.V112.11.5029.5029","article-title":"Time and Dose Dependent Synergism Between Conventional Cytostatics and the p53-Modulating Small Molecule PRIMA-Meth in p53 Mutated Leukemic Cells","volume":"112","author":"Ali","year":"2008","journal-title":"Blood."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Silver, N.L., Osman, A.A., Patel, A.A., Tanaka, N., Tang, L., Zhou, G., and Myers, J.N. (2016). A Novel Third Generation Thiosemicarbazone, COTI-2, Is Highly Effective in Killing Head and Neck Squamous Cell Carcinomas (HNSCC) Bearing a Variety of TP53 Mutations. Int. J. Radiat. Oncol. Biol. Phys., 94.","DOI":"10.1016\/j.ijrobp.2015.12.272"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1093\/carcin\/16.10.2487","article-title":"K-ras mutations in lung tumors from A\/J and A\/J\u00d7TSG-p53 F1 mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and phenethyl isothiocyanate","volume":"16","author":"Matzinger","year":"1995","journal-title":"Carcinogenesis"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"LB006","DOI":"10.1158\/1538-7445.AM2021-LB006","article-title":"Abstract LB006: PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development","volume":"81","author":"Dumble","year":"2021","journal-title":"Cancer Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ccell.2015.07.005","article-title":"Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death","volume":"28","author":"Wang","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"7016","DOI":"10.1038\/sj.onc.1203176","article-title":"Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2\/Bcl-XL, c-Jun, and p21CIP1, but independent of p53","volume":"18","author":"Vrana","year":"1999","journal-title":"Oncogene"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"6332","DOI":"10.1021\/jm500627s","article-title":"Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer","volume":"57","author":"Rew","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"5855","DOI":"10.1158\/0008-5472.CAN-14-0799","article-title":"SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression","volume":"74","author":"Wang","year":"2014","journal-title":"Cancer Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1021\/acs.jmedchem.6b01665","article-title":"Discovery of 4-((3\u2032R,4\u2032S,5\u2032R)-6\u2033-Chloro-4\u2032-(3-chloro-2-fluorophenyl)-1\u2032-ethyl-2\u2033-oxodispiro[cyclohexane-1,2\u2032-pyrrolidine-3\u2032,3\u2033-indoline]-5\u2032-carboxamido)bicyclo [2.2.2]octane-1-carboxylic Acid (AA-115\/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development","volume":"60","author":"Aguilar","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1158\/0008-5472.CAN-17-0949","article-title":"Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition","volume":"78","author":"Ishizawa","year":"2018","journal-title":"Cancer Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"6348","DOI":"10.1021\/acs.jmedchem.5b00810","article-title":"Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors","volume":"58","author":"Holzer","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"4837","DOI":"10.1016\/j.bmcl.2016.08.010","article-title":"Discovery of a novel class of highly potent inhibitors of the p53\u2013MDM2 interaction by structure-based design starting from a conformational argument","volume":"26","author":"Furet","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"6257","DOI":"10.1158\/0008-5472.CAN-18-0338","article-title":"Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53-MDM2 Inhibitor HDM201","volume":"78","author":"Jeay","year":"2018","journal-title":"Cancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.1182\/blood-2022-169021","article-title":"Development of KT-253, a Highly Potent and Selective Heterobifunctional MDM2 Degrader for the Treatment of Acute Myeloid Leukemia","volume":"140","author":"Mayo","year":"2022","journal-title":"Blood"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"9401","DOI":"10.1021\/acs.jmedchem.3c00623","article-title":"Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized \u03b1-Helical Peptide in Clinical Development","volume":"66","author":"Guerlavais","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.apsb.2020.01.003","article-title":"Small-molecule MDM2\/X inhibitors and PROTAC degraders for cancer therapy: Advances and perspectives","volume":"10","author":"Fang","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev-biochem-060815-014710","article-title":"The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches","volume":"85","author":"Joerger","year":"2016","journal-title":"Annu. Rev. Biochem."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1182\/blood.V116.21.657.657","article-title":"A Multi-Center, Open-Label, Phase I Study of Single Agent RG7112, A First In Class p53-MDM2 Antagonist, In Patients with Relapsed\/Refractory Acute Myeloid and Lymphoid Leukemias (AML\/ALL) and Refractory Chronic Lymphocytic Leukemia\/Small Cell Lymphocytic Lymphomas (CLL\/SCLL)","volume":"116","author":"Andreeff","year":"2010","journal-title":"Blood"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"536","DOI":"10.2174\/138161211795222649","article-title":"Small-molecule inhibitors of p53-MDM2 interaction: The 2006\u20132010 update","volume":"17","author":"Millard","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"5979","DOI":"10.1021\/jm400487c","article-title":"Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development","volume":"56","author":"Ding","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1021\/jm401753e","article-title":"Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development","volume":"57","author":"Sun","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.1182\/blood-2018-99-115183","article-title":"Synergistic Anti-Leukemic Activity with Combination of FLT3 Inhibitor Quizartinib and MDM2 Inhibitor Milademetan in FLT3-ITD Mutant\/p53 Wild-Type Acute Myeloid Leukemia Models","volume":"132","author":"Andreeff","year":"2018","journal-title":"Blood"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"6588","DOI":"10.1158\/1538-7445.AM2024-6588","article-title":"Abstract 6588: Discovery of ASTX295, a potent, next-generation small molecule antagonist of MDM2 with differentiated pharmacokinetic profile","volume":"84","author":"Ahn","year":"2024","journal-title":"Cancer Res."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"e9022892","DOI":"10.1097\/01.HS9.0000968764.90228.92","article-title":"P464: Pulse dosing of potent and selective heterobifunctional MDM2 degrader KT-253 drives tumor regression and demonstrates differentiated pharmacology compared to p53\/mdm2 small molecule inhibitors","volume":"7","author":"Schalm","year":"2023","journal-title":"HemaSphere"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1200\/JCO.2017.35.15_suppl.2505","article-title":"Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of <i>WT p53<\/i> in patients with solid tumors and lymphomas","volume":"35","author":"Saleh","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"101155","DOI":"10.1016\/j.gendis.2023.101155","article-title":"Twenty years of Gendicine\u00ae rAd-p53 cancer gene therapy: The first-in-class human cancer gene therapy in the era of personalized oncology","volume":"11","author":"Qi","year":"2024","journal-title":"Genes Dis."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1038\/mt.2016.135","article-title":"Safety and Efficacy in Advanced Solid Tumors of a Targeted Nanocomplex Carrying the p53 Gene Used in Combination with Docetaxel: A Phase 1b Study","volume":"24","author":"Pirollo","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Peng, Y., Bai, J., Li, W., Su, Z., and Cheng, X. (2024). Advancements in p53-Based Anti-Tumor Gene Therapy Research. Molecules, 29.","DOI":"10.3390\/molecules29225315"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.jpba.2012.08.011","article-title":"Determination of cellular uptake and intracellular levels of Cenersen (Aezea\u00ae, EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells","volume":"71","author":"Alachkar","year":"2012","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1158\/0008-5472.CAN-16-3247","article-title":"Development of a T-cell Receptor Mimic Antibody against Wild-Type p53 for Cancer Immunotherapy","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"5382","DOI":"10.1038\/s41467-019-13305-z","article-title":"Targeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen","volume":"10","author":"Low","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"5407","DOI":"10.1158\/0008-5472.CAN-04-0169","article-title":"Two Distinct Pathways of Immuno-Modulation Improve Potency of p53 Immunization in Rejecting Established Tumors","volume":"64","author":"Daftarian","year":"2004","journal-title":"Cancer Res."},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Alvarado-Ortiz, E., de la Cruz-L\u00f3pez, K.G., Becerril-Rico, J., Sarabia-S\u00e1nchez, M.A., Ortiz-S\u00e1nchez, E., and Garc\u00eda-Carranc\u00e1, A. (2020). Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.607670"},{"key":"ref_179","doi-asserted-by":"crossref","unstructured":"Wang, C., Tan, J.Y.M., Chitkara, N., and Bhatt, S. (2024). TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications. Cancers, 16.","DOI":"10.3390\/cancers16173069"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1186\/s12935-021-02396-8","article-title":"p53 signaling in cancer progression and therapy","volume":"21","author":"Marei","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13046-018-0705-7","article-title":"New therapeutic strategies to treat human cancers expressing mutant p53 proteins","volume":"37","author":"Blandino","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41392-023-01347-1","article-title":"Targeting p53 pathways: Mechanisms, structures and advances in therapy","volume":"8","author":"Wang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.tig.2022.02.010","article-title":"The p53 network: Cellular and systemic DNA damage responses in cancer and aging","volume":"38","author":"Vaddavalli","year":"2022","journal-title":"Trends Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12928\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:44:20Z","timestamp":1760114660000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12928"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,1]]},"references-count":183,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252312928"],"URL":"https:\/\/doi.org\/10.3390\/ijms252312928","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,1]]}}}