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

• DOI: 10.1016/j.celrep.2014.03.047
• Publication Date: 2014-04-18T01:30:04Z
• Authors: 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
• Keywords: Mediator; Cyclin-dependent kinase 8; Cyclin D; Cyclin A

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