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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations in exon 1 highlight the role of MED12 in uterine leiomyomas
Human Mutation, Volume 35, No. 9, Year 2014
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Description
Mediator regulates transcription by connecting gene-specific transcription factors to the RNA polymerase II initiation complex. We recently discovered by exome sequencing that specific exon 2 mutations in mediator complex subunit 12 (MED12) are extremely common in uterine leiomyomas. Subsequent screening studies have focused on this mutational hot spot, and mutations have been detected in uterine leiomyosarcomas, extrauterine leiomyomas and leiomyosarcomas, endometrial polyps, and colorectal cancers. All mutations have been missense changes or in-frame insertions/deletions. Here, we have analyzed 611 samples representing all above-mentioned tumor types for possible exon 1 mutations. Five mutations were observed, all of which were in-frame insertion/deletions in uterine leiomyomas. Transcriptome-wide expression data revealed that MED12 exon 1 and exon 2 mutations lead to the same unique global gene expression pattern with RAD51B being the most upregulated gene. Immunoprecipitation and kinase activity assays showed that both exon 1 and exon 2 mutations disrupt the interaction between MED12 and Cyclin C and CDK8/19 and abolish the mediator-associated CDK kinase activity. These results further emphasize the role of MED12 in uterine leiomyomas, show that exon 1 and exon 2 exert their tumorigenic effect in similar manner, and stress that exon 1 should be included in subsequent MED12 screenings. © 2014 WILEY PERIODICALS, INC.
Authors & Co-Authors
Kämpjärvi, Kati
Finland, Helsinki
Helsingin Yliopisto
Park, Min Ju
United States, San Antonio
University of Texas Health Science Center at San Antonio
Mehine, Miika
Finland, Helsinki
Helsingin Yliopisto
Kim, Nam Hee
United States, San Antonio
University of Texas Health Science Center at San Antonio
Clark, Alison D.
United States, San Antonio
University of Texas Health Science Center at San Antonio
Bützow, Ralf
Finland, Helsinki
Helsinki University Hospital
Böhling, Tom
Finland, Helsinki
Helsinki University Hospital
Böhm, Jan P.
Finland, Jyvaskyla
Jyvaskyla Central Hospital
Mecklin, Jukka Pekka
Finland, Kuopio
Itä-suomen Yliopisto
Järvinen, Heikki Juhani J.
Finland, Helsinki
Helsinki University Hospital
Tomlinson, Ian P.M.
United Kingdom, Oxford
Nuffield Department of Medicine
van der Spuy, Zephne M.
South Africa, Cape Town
Faculty of Health Sciences
Sjöberg, Jari
Finland, Helsinki
Helsinki University Hospital
Boyer, Thomas G.
United States, San Antonio
University of Texas Health Science Center at San Antonio
Vahteristo, Pia
Finland, Helsinki
Helsingin Yliopisto
Statistics
Citations: 73
Authors: 15
Affiliations: 7
Identifiers
Doi:
10.1002/humu.22612
ISSN:
10597794
e-ISSN:
10981004
Research Areas
Cancer
Genetics And Genomics