{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:22:48Z","timestamp":1791206568218,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,9,18]],"date-time":"2015-09-18T00:00:00Z","timestamp":1442534400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["260370"],"award-info":[{"award-number":["260370"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["265124"],"award-info":[{"award-number":["265124"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9lius Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006383","name":"Cancer Society of Finland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006383","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003756","name":"Biomedicum Helsinki Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003756","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007083","name":"Orion Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007083","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention Research Institute of Texas","doi-asserted-by":"publisher","award":["RP140435"],"award-info":[{"award-number":["RP140435"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["T32DE014318"],"award-info":[{"award-number":["T32DE014318"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Mediator is a multiprotein interface between eukaryotic gene\u2010specific transcription factors and RNA polymerase II. Mutations in exon 2 of the gene encoding MED12, a key subunit of the regulatory kinase module in Mediator, are extremely frequent in uterine leiomyomas, breast fibroadenomas, and phyllodes tumors. These mutations disrupt kinase module interactions and lead to diminished Mediator\u2010associated kinase activity. <jats:italic>MED12<\/jats:italic> mutations in exon 26, resulting in a substitution of leucine 1224 to phenylalanine (L1224F), have been recurrently observed in prostate cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>To elucidate the molecular mechanisms leading to tumorigenesis in prostate cancer, we analyzed global interaction profiles of wild\u2010type and L1224F mutant MED12 with quantitative affinity purification\u2010mass spectrometry (AP\u2010MS). Immunoprecipitation and kinase activity assay were used to further assess the interactions between Mediator complex subunits and kinase activity. The presence of L1224F mutation was analyzed in altogether 877 samples representing prostate hyperplasia, prostate cancer, and various tumor types in which somatic <jats:italic>MED12<\/jats:italic> mutations have previously been observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In contrast to N\u2010terminal MED12 mutations observed in uterine leiomyomas, the L1224F mutation compromises neither the interaction of MED12 with kinase module subunits Cyclin C and CDK8\/19 nor Mediator\u2010associated CDK activity. Instead, the L1224F mutation was shown to affect interactions between MED12 and other Mediator components (MED1, MED13, MED13L, MED14, MED15, MED17, and MED24). Mutation screening revealed one mutation in a Finnish (Caucasian) prostate cancer patient, whereas no mutations in any other tumor type were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Specific somatic <jats:italic>MED12<\/jats:italic> mutations in prostate cancer and uterine leiomyomas accumulate in two separate regions of the gene and promote tumorigenesis through clearly distinct mechanisms. <jats:italic>Prostate 76:22\u201331, 2016<\/jats:italic>. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.23092","type":"journal-article","created":{"date-parts":[[2015,9,18]],"date-time":"2015-09-18T10:33:17Z","timestamp":1442572397000},"page":"22-31","source":"Crossref","is-referenced-by-count":43,"title":["Somatic <i>MED12<\/i> mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms"],"prefix":"10.1002","volume":"76","author":[{"given":"Kati","family":"K\u00e4mpj\u00e4rvi","sequence":"first","affiliation":[{"name":"Genome\u2010Scale Biology Research Program and Department of Medical and Clinical Genetics University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Institute of Biotechnology, University of Texas Health Science Center at San Antonio San Antonio Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salla","family":"Keskitalo","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison D.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Institute of Biotechnology, University of Texas Health Science Center at San Antonio San Antonio Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pernilla","family":"von Nandelstadh","sequence":"additional","affiliation":[{"name":"Genome\u2010Scale Biology Research Program and Department of Pathology University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko","family":"Turunen","sequence":"additional","affiliation":[{"name":"Genome\u2010Scale Biology Research Program and Department of Pathology University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas","family":"Heikkinen","sequence":"additional","affiliation":[{"name":"Genome\u2010Scale Biology Research Program and Department of Medical and Clinical Genetics University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Ju","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Institute of Biotechnology, University of Texas Health Science Center at San Antonio San Antonio Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Netta","family":"M\u00e4kinen","sequence":"additional","affiliation":[{"name":"Genome\u2010Scale Biology Research Program and Department of Medical and Clinical Genetics University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kati","family":"Kivinummi","sequence":"additional","affiliation":[{"name":"Institute of Biosciences and Medical Technology \u2010 BioMediTech and Fimlab Laboratories University of Tampere and Tampere University Hospital Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Lintula","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Hotakainen","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heli","family":"Nevanlinna","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Helsinki and Helsinki University Central Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hokland","sequence":"additional","affiliation":[{"name":"Department of Hematology Aarhus University Hospital Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"B\u00f6hling","sequence":"additional","affiliation":[{"name":"Department of Pathology The Laboratory of Helsinki University Central Hospital (HUSLAB), Helsinki University Central Hospital and Medicum, University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"B\u00fctzow","sequence":"additional","affiliation":[{"name":"Department of Pathology The Laboratory of Helsinki University Central Hospital (HUSLAB), Helsinki University Central Hospital and Medicum, University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"Department of Pathology Jyv\u00e4skyl\u00e4 Central Hospital Jyv\u00e4skyl\u00e4 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka\u2010Pekka","family":"Mecklin","sequence":"additional","affiliation":[{"name":"Department of Surgery Jyv\u00e4skyl\u00e4 Central Hospital and University of Eastern Finland Jyv\u00e4skyl\u00e4 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikki","family":"J\u00e4rvinen","sequence":"additional","affiliation":[{"name":"Department of Surgery Helsinki University Central Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Kontro","sequence":"additional","affiliation":[{"name":"Hematology Research Unit Helsinki, Department of Medicine Helsinki University Central Hospital and University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tapio","family":"Visakorpi","sequence":"additional","affiliation":[{"name":"Institute of Biosciences and Medical Technology \u2010 BioMediTech and Fimlab Laboratories University of Tampere and Tampere University Hospital Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jussi","family":"Taipale","sequence":"additional","affiliation":[{"name":"Genome\u2010Scale Biology Research Program and Department of Pathology University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markku","family":"Varjosalo","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Boyer","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Institute of Biotechnology, University of Texas Health Science Center at San Antonio San Antonio Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Vahteristo","sequence":"additional","affiliation":[{"name":"Genome\u2010Scale Biology Research Program and Department of Medical and Clinical Genetics University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,9,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2010.02.004"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2011.01.013"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2011.07.021"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn349"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/trns.1.1.12373"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1208930"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22612"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1302736"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.03.047"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27610"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.428"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0040015"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2012.203"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3037"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2753"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-14-0578"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2279"},{"key":"e_1_2_7_19_1","unstructured":"The International Cancer Genome Consortium. ICGC data portal 3.8.5.6. Available at:https:\/\/dcc.icgc.org\/mutations\/MU1677739. Accessed 06\/10\/2015."},{"key":"e_1_2_7_20_1","unstructured":"FerlayJ SoerjomataramI ErvikM DikshitR EserS MathersC RebeloM ParkinD FormanD BrayF.GLOBOCAN 2012 v1.0 cancer incidence and mortality worldwide: IARC CancerBase No. 11. Available at:http:\/\/globocan.iarc.fr\/Pages\/fact_sheets_cancer.aspx. Accessed 06\/10\/2015."},{"key":"e_1_2_7_21_1","unstructured":"HowladerN NooneA KrapchoM GarshellJ MillerD AltekruseS KosaryC YuM RuhlJ TatalovichZ MariottoA LewisD ChenH FeuerE CroninK.SEER cancer statistics review 1975\u20102012 National Cancer Institute. Bethesda MD. Available at:http:\/\/seer.cancer.gov\/statfacts\/html\/prost.html. Accessed 06\/10\/2015."},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.03.027"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.01.007"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M602696200"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206061200"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.304519"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3039"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-12-0618"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28647"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-14-0171"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.10.035"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.11.007"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.29339"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2536"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4208"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11125"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2012.11.053"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4208"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1075"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12912"}],"container-title":["The Prostate"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpros.23092","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpros.23092","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pros.23092","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T17:34:50Z","timestamp":1696527290000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pros.23092"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,18]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,1]]}},"alternative-id":["10.1002\/pros.23092"],"URL":"https:\/\/doi.org\/10.1002\/pros.23092","archive":["Portico"],"relation":{},"ISSN":["0270-4137","1097-0045"],"issn-type":[{"value":"0270-4137","type":"print"},{"value":"1097-0045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9,18]]}}}