Mutations in Exon 1 Highlight the Role of MED12 in Uterine Leiomyomas
| Autor: | Tom Böhling, Thomas G. Boyer, Heikki Järvinen, Jari Sjöberg, Pia Vahteristo, Kati Kämpjärvi, Ralf Bützow, Miika Mehine, Min Ju Park, Jan Böhm, Nam Hee Kim, Alison D. Clark, Jukka-Pekka Mecklin, Ian Tomlinson, Zephne M van der Spuy |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
RNA polymerase II
Cell Line MED12 03 medical and health sciences Exon 0302 clinical medicine Germline mutation Cyclin-dependent kinase Genetics Cluster Analysis Humans Missense mutation Kinase activity Gene Genetic Association Studies Genetics (clinical) 030304 developmental biology 0303 health sciences Mediator Complex Leiomyoma biology Gene Expression Profiling Exons Molecular biology 3. Good health Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Mutation Uterine Neoplasms biology.protein Cancer research Female Protein Binding |
| Popis: | 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. Uterine leiomyomas are the most common human tumors with highly specific mutations reported in MED12 exon 2. Here, we show that mutations occur recurrently also in MED12 exon 1. Transcriptome-wide gene expression profiling and functional analyses show that exon 1 and 2 mutations promote tumorigenesis through similar mechanism. These results bring new knowledge on MED12 function and highlight the role of MED12 in human tumorigenesis. © 2014 WILEY PERIODICALS, INC. |
| Databáze: | OpenAIRE |
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