{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:42:03Z","timestamp":1792154523181,"version":"4.4.0"},"reference-count":70,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"707","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,8,2]]},"abstract":"<jats:p>\n            Although alternative splicing (AS) drives transcriptional responses and cellular adaptation to environmental stresses, its contributions in organ transplantation have not been appreciated. We have shown that carcinoembryonic antigen\u2013related cell adhesion molecule (Ceacam1;\n            <jats:italic>CD66a<\/jats:italic>\n            ), a transmembrane biliary glycoprotein expressed in epithelial, endothelial, and immune cells, determines donor liver transplant quality. Here, we studied how AS of\n            <jats:italic>Ceacam1<\/jats:italic>\n            affects ischemia-reperfusion injury (IRI) in mouse and human livers. We found that the short cytoplasmic isoform\n            <jats:italic>Ceacam1-S<\/jats:italic>\n            increased during early acute and late resolution phases of warm IRI injury in mice. Transfection of Ceacam1-deficient mouse hepatocytes with adenoviral Ceacam1-S mitigated hypoxia-induced loss of cellular adhesion by repressing the Ask1\/p-p38 cell death pathway. Nucleic acid\u2013blocking morpholinos, designed to selectively induce Ceacam1-S, protected hepatocyte cultures against temperature-induced stress in vitro. Luciferase and chromatin immunoprecipitation assays identified direct binding of hypoxia-inducible factor\u20131\u03b1 (Hif-1\u03b1) to the mouse polypyrimidine tract binding protein 1 (\n            <jats:italic>Ptbp1<\/jats:italic>\n            ) promoter region. Dimethyloxalylglycine protected mouse livers from warm IR stress and hepatocellular damage by inhibiting prolyl hydroxylase domain\u2013containing protein 1 and promoting AS of\n            <jats:italic>Ceacam1-S<\/jats:italic>\n            . Last, analysis of 46 human donor liver grafts revealed that\n            <jats:italic>CEACAM1-S<\/jats:italic>\n            positively correlated with pretransplant\n            <jats:italic>HIF1A<\/jats:italic>\n            expression. This also correlated with better transplant outcomes, including reduced\n            <jats:italic>TIMP1<\/jats:italic>\n            , total bilirubin, proinflammatory\n            <jats:italic>MCP1<\/jats:italic>\n            ,\n            <jats:italic>CXCL10<\/jats:italic>\n            cytokines, immune activation markers\n            <jats:italic>IL17A<\/jats:italic>\n            , and incidence of delayed complications from biliary anastomosis. This translational study identified mouse Hif-1\u03b1\u2013controlled AS of\n            <jats:italic>Ceacam1<\/jats:italic>\n            , through transcriptional regulation of\n            <jats:italic>Ptbp1<\/jats:italic>\n            promoter region, as a functional underpinning of hepatoprotection against IR stress and tissue damage in liver transplantation.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adf2059","type":"journal-article","created":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T17:58:55Z","timestamp":1690999135000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":33,"title":["Alternative splicing of CEACAM1 by hypoxia-inducible factor\u20131\u03b1 enhances tolerance to hepatic ischemia in mice and humans"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4238-4092","authenticated-orcid":true,"given":"Kenneth J.","family":"Dery","sequence":"first","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenobu","family":"Kojima","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2398-2428","authenticated-orcid":true,"given":"Shoichi","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Kadono","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6975-2436","authenticated-orcid":true,"given":"Hirofumi","family":"Hirao","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhai","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9080-0527","authenticated-orcid":true,"given":"Douglas G.","family":"Farmer","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4888-3979","authenticated-orcid":true,"given":"Fady M.","family":"Kaldas","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2898-6495","authenticated-orcid":true,"given":"Xiaoyi","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, McGovern Medical School at UTHealth, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger K.","family":"Eltzschig","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, McGovern Medical School at UTHealth, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8976-4872","authenticated-orcid":true,"given":"Jerzy W.","family":"Kupiec-Weglinski","sequence":"additional","affiliation":[{"name":"Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00133"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20100396"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1683-5"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2004-5-10-r74"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.20294"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI133142"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-13-64"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.204057"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)54060-6"},{"key":"e_1_3_2_11_2","first-page":"e1328336","article-title":"CEACAM1 as a multi-purpose target for cancer 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D.\u00a0Gray-Owen, Y. H.\u00a0Huang, R. S.\u00a0Blumberg, N.\u00a0Beauchemin, CEACAM1 as a multi-purpose target for cancer immunotherapy. Oncoimmunology 6, e1328336 (2017).","journal-title":"Oncoimmunology"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2008.50"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2019.101296"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001507"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80426-8"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.shk.0000170352.72694.36"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119533"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/lt.24352"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31093"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S275000"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-020-01616-9"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg605"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-81383-5"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI136679"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2018.02.005"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-013-9444-6"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.496992"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)00222-1"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610903200"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210577"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1999.277.2.C183"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-6386(99)70252-0"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/s001470050502"},{"key":"e_1_3_2_34_2","first-page":"1757","article-title":"Expression of fibronectin splicing variants in organ transplantation: A differential pattern between rat cardiac allografts and isografts","volume":"150","author":"Coito A. 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(National Academies Press 2011)."},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.08.010"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.11.026"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1002\/lt.20489"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00482.2007"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199306000-00011"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adf2059","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T17:57:54Z","timestamp":1705427874000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adf2059"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,2]]},"references-count":70,"journal-issue":{"issue":"707","published-print":{"date-parts":[[2023,8,2]]}},"alternative-id":["10.1126\/scitranslmed.adf2059"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adf2059","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,2]]},"assertion":[{"value":"2022-10-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadf2059"}}