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Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity.
Cell Rep. 2014 May 08; 7(3):654-60.CR

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.

Authors+Show Affiliations

Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA.Institute of Biotechnology, University of Helsinki, Viikinkaari 1, P.O. Box 65, Helsinki FIN-00014, Finland.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA.Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland; Department of Computer Science, University of Helsinki, P.O. Box 68, Helsinki FIN-00014, Finland.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA.Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA.Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.Institute of Biotechnology, University of Helsinki, Viikinkaari 1, P.O. Box 65, Helsinki FIN-00014, Finland.Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland; Science for Life Laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm 14183, Sweden.Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.Department of Biochemistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.Institute of Biotechnology, University of Helsinki, Viikinkaari 1, P.O. Box 65, Helsinki FIN-00014, Finland. Electronic address: markku.varjosalo@helsinki.fi.Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland; Science for Life Laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm 14183, Sweden. Electronic address: jussi.taipale@ki.se.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA. Electronic address: boyer@uthscsa.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24746821

Citation

Turunen, Mikko, et al. "Uterine Leiomyoma-linked MED12 Mutations Disrupt Mediator-associated CDK Activity." Cell Reports, vol. 7, no. 3, 2014, pp. 654-60.
Turunen M, Spaeth JM, Keskitalo S, et al. Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity. Cell Rep. 2014;7(3):654-60.
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), 654-60. https://doi.org/10.1016/j.celrep.2014.03.047
Turunen M, et al. Uterine Leiomyoma-linked MED12 Mutations Disrupt Mediator-associated CDK Activity. Cell Rep. 2014 May 8;7(3):654-60. PubMed PMID: 24746821.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity. AU - Turunen,Mikko, AU - Spaeth,Jason M, AU - Keskitalo,Salla, AU - Park,Min Ju, AU - Kivioja,Teemu, AU - Clark,Alison D, AU - Mäkinen,Netta, AU - Gao,Fangjian, AU - Palin,Kimmo, AU - Nurkkala,Helka, AU - Vähärautio,Anna, AU - Aavikko,Mervi, AU - Kämpjärvi,Kati, AU - Vahteristo,Pia, AU - Kim,Chongwoo A, AU - Aaltonen,Lauri A, AU - Varjosalo,Markku, AU - Taipale,Jussi, AU - Boyer,Thomas G, Y1 - 2014/04/18/ PY - 2013/10/18/received PY - 2014/01/23/revised PY - 2014/03/18/accepted PY - 2014/4/22/entrez PY - 2014/4/22/pubmed PY - 2015/1/6/medline SP - 654 EP - 60 JF - Cell reports JO - Cell Rep VL - 7 IS - 3 N2 - 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. SN - 2211-1247 UR - https://www.unboundmedicine.com/medline/citation/24746821/Uterine_leiomyoma_linked_MED12_mutations_disrupt_mediator_associated_CDK_activity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-1247(14)00244-7 DB - PRIME DP - Unbound Medicine ER -