{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:25:07Z","timestamp":1747185907202,"version":"3.40.5"},"reference-count":57,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54MD015929"],"award-info":[{"award-number":["U54MD015929"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Acute promyelocytic leukaemia (APL) occurs in approximately 10% of acute myeloid leukaemia patients. Arsenic trioxide (ATO) has been for APL chemotherapy, but recently several ATO\u2010resistant cases have been reported worldwide. Cisplatin (CDDP) enhances the toxicity of ATO in ovarian, lung cancer, chronic myelogenous leukaemia, and HL\u201060 cells. Hence, the goal of this study was to investigate a novel target of CDDP action in APL cells, as an alternate option for the treatment of ATO\u2010resistant APL patients. We applied biochemical, molecular, confocal microscopy and advanced gene editing (CRISPR\u2010Cas9) techniques to elucidate the novel target of CDDP action and its functional mechanism in APL cells. Our main findings revealed that CDDP activated p53 in APL cells through stress signals catalysed by ATM and ATR protein kinases, CHK1 and CHK2 phosphorylation at Ser 345 and Thr68 residues, and downregulation and dissociation of MDM2\u2010DAXX\u2010HAUSP complex. Our functional studies confirmed that CDDP\u2010induced repression of MDM2\u2010DAXX\u2010HAUSP complex was significantly reversed in both nutilin\u20103\u2010treated KG1a and p53\u2010knockdown NB4 cells. Our findings also showed that CDDP stimulated an increased number of promyelocytes with dense granules, activated p53 expression, and downregulated MDM2 in liver and bone marrow of APL mice. Principal conclusion of our study highlights a novel mode of action of CDDP targeting p53 expression which may provide a basis for designing new anti\u2010leukaemic compounds for treatment of APL patients.<\/jats:p>","DOI":"10.1111\/jcmm.17502","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T05:45:52Z","timestamp":1660110352000},"page":"4727-4739","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["p53 as a unique target of action of cisplatin in acute leukaemia cells"],"prefix":"10.1111","volume":"26","author":[{"given":"Sanjay","family":"Kumar","sequence":"first","affiliation":[{"name":"Cellomics and Toxicogenomics Research Laboratory, NIH\/NIMHD\u2010RCMI Center for Health Disparities Research Jackson State University  Jackson Mississippi USA"},{"name":"Department of life Sciences, School of Earth, Biological, and Environmental Sciences Central University South Bihar  Gaya 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