Uterine Leiomyoma-Linked MED12 Mutations Disrupt Mediator-Associated CDK Activity

Mikko Turunen, Jason M. Spaeth, Salla Keskitalo, Min Ju Park, Teemu Kivioja, Alison D. Clark, Netta Mäkinen, Fangjian Gao, Kimmo Palin, Helka Nurkkala, Anna Vähärautio, Mervi Aavikko, Kati Kämpjärvi, Pia Vahteristo, Chongwoo A. Kim, Lauri A. Aaltonen, Markku Varjosalo, Jussi Taipale, Thomas G. Boyer

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at very high frequency (~70%) in uterine leiomyomas. However, the influence of these mutations on Mediator function and the molecular basis for their tumorigenic potential remain unknown. To clarify the impact of these mutations, we used affinity-purification mass spectrometry to establish the global protein-protein interaction profiles for both wild-type and mutant MED12. We found that uterine leiomyoma-linked mutations in MED12 led to a highly specific decrease in its association with Cyclin C-CDK8/CDK19 and loss of Mediator-associated CDK activity. Mechanistically, this occurs through disruption of a MED12-Cyclin C binding interface that we also show is required for MED12-mediated stimulation of Cyclin C-dependent CDK8 kinase activity. These findings indicate that uterine leiomyoma-linked mutations in MED12 uncouple Cyclin C-CDK8/19 from core Mediator and further identify the MED12/Cyclin C interface as a prospective therapeutic target in CDK8-driven cancers.

Original languageEnglish (US)
Pages (from-to)654-660
Number of pages7
JournalCell Reports
Volume7
Issue number3
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Turunen, M., Spaeth, J. M., Keskitalo, S., Park, M. J., Kivioja, T., Clark, A. D., Mäkinen, N., Gao, F., Palin, K., Nurkkala, H., Vähärautio, A., Aavikko, M., Kämpjärvi, K., Vahteristo, P., Kim, C. A., Aaltonen, L. A., Varjosalo, M., Taipale, J., & Boyer, T. G. (2014). Uterine Leiomyoma-Linked MED12 Mutations Disrupt Mediator-Associated CDK Activity. Cell Reports, 7(3), 654-660. https://doi.org/10.1016/j.celrep.2014.03.047