{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:54:23Z","timestamp":1717721663616},"reference-count":26,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2009,5,26]],"date-time":"2009-05-26T00:00:00Z","timestamp":1243296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The <jats:italic>TP53<\/jats:italic> tumor suppressor gene is the most frequently inactivated gene in human cancer identified to date. However, <jats:italic>TP53<\/jats:italic> mutations are rare in human mesotheliomas, as well as in many other types of cancer, suggesting that aberrant <jats:italic>TP53<\/jats:italic> function may be due to alterations in its regulatory pathways. <jats:italic>Mouse double minute 4<\/jats:italic> (<jats:italic>MDM4<\/jats:italic>) has been shown to be a key regulator of <jats:italic>TP53<\/jats:italic> activity, both independently as well as in concert with its structural homolog, <jats:italic>Mouse Double Minute 2<\/jats:italic> (<jats:italic>MDM2<\/jats:italic>). The purpose of this study was to characterize the effects of <jats:italic>MDM4<\/jats:italic> suppression on <jats:italic>TP53<\/jats:italic> and other proteins involved in cell cycle control before and after ultraviolet (UV) exposure in MeT5a cells, a nonmalignant human mesothelial line. Short hairpin RNA (shRNA) was used to investigate the impact of <jats:italic>MDM4<\/jats:italic> on <jats:italic>TP53<\/jats:italic> function and cellular transcription. Suppression of <jats:italic>MDM4<\/jats:italic> was confirmed by Western blot. <jats:italic>MDM4<\/jats:italic> suppressed cells were analyzed for cell cycle changes with and without exposure to UV. Changes in cell growth as well as differences in the regulation of direct transcriptional targets of <jats:italic>TP53<\/jats:italic>, <jats:italic>CDKN1A<\/jats:italic> (cyclin\u2010dependent kinase 1\u03b1, <jats:italic>p21<\/jats:italic>) and <jats:italic>BAX<\/jats:italic>, suggest a shift from cell cycle arrest to apoptosis upon increasing UV exposure. These results demonstrate the importance of <jats:italic>MDM4<\/jats:italic>in cell cycle regulation as well as a possible role inthe pathogenesis of mesothelioma\u2010type cancers. Environ. Mol. Mutagen. 2009. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/em.20498","type":"journal-article","created":{"date-parts":[[2009,5,26]],"date-time":"2009-05-26T19:13:36Z","timestamp":1243365216000},"page":"753-759","source":"Crossref","is-referenced-by-count":2,"title":["Suppression of the mouse double minute 4 gene causes changes in cell cycle control in a human mesothelial cell line responsive to ultraviolet radiation exposure"],"prefix":"10.1002","volume":"50","author":[{"given":"Melisa","family":"Bunderson\u2010Schelvan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy K.","family":"Erbe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corbin","family":"Schwanke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Pershouse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,5,26]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1297-453"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.01.020"},{"key":"e_1_2_1_4_1","first-page":"8664","article-title":"Switching mechanisms of cell death in MDM2\u2010 and MDM4\u2010null mice by deletion of TP53 downstream targets","volume":"63","author":"Chavez\u2010Reyes A","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.13.5835-5843.2004"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90500-P"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508476103"},{"key":"e_1_2_1_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90499-G"},{"key":"e_1_2_1_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2005.08.008"},{"key":"e_1_2_1_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01198-07"},{"key":"e_1_2_1_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1352206"},{"key":"e_1_2_1_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2007.01.003"},{"key":"e_1_2_1_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311793200"},{"key":"e_1_2_1_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.03.151"},{"key":"e_1_2_1_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(01)00264-7"},{"key":"e_1_2_1_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90412-3"},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(99)00487-4"},{"key":"e_1_2_1_18_1","first-page":"2","article-title":"P27kip1: A target for tumor therapies?","volume":"9","author":"Nickeleit I","year":"2007","journal-title":"Cell Div"},{"key":"e_1_2_1_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng714"},{"key":"e_1_2_1_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408595102"},{"key":"e_1_2_1_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-008-0322-6"},{"key":"e_1_2_1_22_1","first-page":"1679","article-title":"Expression of CDKN1A(Waf1\/Cip1), p57(Kip2) and HER2\/new in patients with gallbladder cancer","volume":"27","author":"Puhalla H","year":"2007","journal-title":"Anticancer Res"},{"key":"e_1_2_1_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205404"},{"key":"e_1_2_1_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11023"},{"key":"e_1_2_1_25_1","doi-asserted-by":"crossref","first-page":"28039","DOI":"10.1074\/jbc.M003496200","article-title":"Hdmx stabilizes MDM2 and TP53","volume":"275","author":"Stad R","year":"2000","journal-title":"J Biol Chem"},{"key":"e_1_2_1_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206925"},{"key":"e_1_2_1_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-4129"}],"container-title":["Environmental and Molecular Mutagenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fem.20498","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/em.20498","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T23:36:04Z","timestamp":1699918564000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/em.20498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5,26]]},"references-count":26,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["10.1002\/em.20498"],"URL":"https:\/\/doi.org\/10.1002\/em.20498","archive":["Portico"],"relation":{},"ISSN":["0893-6692","1098-2280"],"issn-type":[{"value":"0893-6692","type":"print"},{"value":"1098-2280","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,5,26]]}}}