{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T16:35:44Z","timestamp":1789403744122,"version":"build-2803163510"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T00:00:00Z","timestamp":1529020800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T00:00:00Z","timestamp":1529020800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["R01CA175691"],"award-info":[{"award-number":["R01CA175691"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["CA06927"],"award-info":[{"award-number":["CA06927"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:p>\n                    Malignant mesothelioma (MM) is a therapy\u2010resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin\u2010dependent kinase inhibitor 2A (\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    ), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1\u2010associated protein 1 (\n                    <jats:italic>BAP1<\/jats:italic>\n                    ), and neurofibromatosis 2 (\n                    <jats:italic>NF2<\/jats:italic>\n                    ). Furthermore, the p53 gene (\n                    <jats:italic>TP53<\/jats:italic>\n                    ) itself is mutated in ~15% of MMs. In many MMs, the PI3K\u2013PTEN\u2013AKT\u2013mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance. Here, we demonstrate that the inactivation of both\n                    <jats:italic>Tp53<\/jats:italic>\n                    and\n                    <jats:italic>Pten<\/jats:italic>\n                    in the mouse mesothelium is sufficient to rapidly drive aggressive MMs.\n                    <jats:italic>Pten<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>L\/L<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>;Tp53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>L\/L<\/jats:italic>\n                    <\/jats:sup>\n                    mice injected intraperitoneally or intrapleurally with adenovirus\u2010expressing Cre recombinase developed high rates of peritoneal and pleural MMs (92% of mice with a median latency of 9.4 weeks and 56% of mice with a median latency of 19.3 weeks, respectively). MM cells from these mice showed consistent activation of Akt\u2013mTor signaling, chromosome breakage or aneuploidy, and upregulation of Myc; occasional downregulation of Bap1 was also observed. Collectively, these findings suggest that when\n                    <jats:italic>Pten<\/jats:italic>\n                    and\n                    <jats:italic>Tp53<\/jats:italic>\n                    are lost in combination in mesothelial cells, DNA damage is not adequately repaired and genomic instability is widespread, whereas the activation of Akt due to\n                    <jats:italic>Pten<\/jats:italic>\n                    loss protects genomically damaged cells from apoptosis, thereby increasing the likelihood of tumor formation. Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed\u00a0codeletions of\n                    <jats:italic>PTEN<\/jats:italic>\n                    and\n                    <jats:italic>TP53<\/jats:italic>\n                    and\/or\n                    <jats:italic>CDKN2A\/p14ARF<\/jats:italic>\n                    in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention.\n                  <\/jats:p>","DOI":"10.1002\/jcp.26830","type":"journal-article","created":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T03:19:21Z","timestamp":1529032761000},"page":"8952-8961","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Inactivation of\n                    <i>Tp53<\/i>\n                    and\n                    <i>Pten<\/i>\n                    drives rapid development of pleural and peritoneal malignant mesotheliomas"],"prefix":"10.1002","volume":"233","author":[{"given":"Eleonora","family":"Sementino","sequence":"first","affiliation":[{"name":"Cancer Biology Program Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8305-9811","authenticated-orcid":false,"given":"Craig W.","family":"Menges","sequence":"additional","affiliation":[{"name":"Cancer Biology Program Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwaraj","family":"Kadariya","sequence":"additional","affiliation":[{"name":"Cancer Biology Program Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suraj","family":"Peri","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfei","family":"Xu","sequence":"additional","affiliation":[{"name":"Cancer Biology Program Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zemin","family":"Liu","sequence":"additional","affiliation":[{"name":"Cancer Biology Program Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard G.","family":"Wilkes","sequence":"additional","affiliation":[{"name":"Cancer Biology Program Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy Q.","family":"Cai","sequence":"additional","affiliation":[{"name":"Histopathology Facility Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Frank J.","family":"Rauscher","sequence":"additional","affiliation":[{"name":"Gene Expression and Regulation Program Wistar Institute  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres J.","family":"Klein\u2010Szanto","sequence":"additional","affiliation":[{"name":"Histopathology Facility Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1301-5175","authenticated-orcid":false,"given":"Joseph R.","family":"Testa","sequence":"additional","affiliation":[{"name":"Cancer Biology Program Fox Chase Cancer Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,6,15]]},"reference":[{"key":"e_1_2_7_1_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-012-0615-9"},{"key":"e_1_2_7_1_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2312"},{"key":"e_1_2_7_1_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208744"},{"key":"e_1_2_7_1_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M709698200"},{"key":"e_1_2_7_1_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10275"},{"key":"e_1_2_7_1_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.24.10854"},{"key":"e_1_2_7_1_8_1","doi-asserted-by":"publisher","DOI":"10.1078\/0344-0338-00427"},{"key":"e_1_2_7_1_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.855"},{"key":"e_1_2_7_1_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3520"},{"key":"e_1_2_7_1_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2016.03.001"},{"key":"e_1_2_7_1_12_1","first-page":"5547","article-title":"p16 alterations and deletion mapping of 9p21\u2010p22 in malignant mesothelioma","volume":"54","author":"Cheng J. 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