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

doi:10.1016/j.celrep.2014.03.047

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

Department of Molecular Medicine

Research output: Contribution to journal › Article › peer-review

122 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 language	English (US)
Pages (from-to)	654-660
Number of pages	7
Journal	Cell Reports
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2014.03.047
State	Published - 2014

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2014.03.047

Cite this

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

Turunen, M, Spaeth, JM, Keskitalo, S, Park, MJ, Kivioja, T, Clark, AD, Mäkinen, N, Gao, F, Palin, K, Nurkkala, H, Vähärautio, A, Aavikko, M, Kämpjärvi, K, Vahteristo, P, Kim, CA, Aaltonen, LA, Varjosalo, M, Taipale, J & Boyer, TG 2014, 'Uterine Leiomyoma-Linked MED12 Mutations Disrupt Mediator-Associated CDK Activity', Cell Reports, vol. 7, no. 3, pp. 654-660. https://doi.org/10.1016/j.celrep.2014.03.047

@article{6c8a3d7d028545808caf8bdea5fbfbe1,

title = "Uterine Leiomyoma-Linked MED12 Mutations Disrupt Mediator-Associated CDK Activity",

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.",

author = "Mikko Turunen and Spaeth, {Jason M.} and Salla Keskitalo and Park, {Min Ju} and Teemu Kivioja and Clark, {Alison D.} and Netta M{\"a}kinen and Fangjian Gao and Kimmo Palin and Helka Nurkkala and Anna V{\"a}h{\"a}rautio and Mervi Aavikko and Kati K{\"a}mpj{\"a}rvi and Pia Vahteristo and Kim, {Chongwoo A.} and Aaltonen, {Lauri A.} and Markku Varjosalo and Jussi Taipale and Boyer, {Thomas G.}",

note = "Funding Information: We thank Dr. Mikael Bj{\"o}rklund for critical review of the manuscript and Hertta Perikangas-Hentunen, Sini Miettinen, and Michael Parker for technical assistance. This work was supported by the Academy of Finland Center of Excellence in Cancer Genetics, Finnish Cancer Organizations, Sigrid Juselius Foundation, Biocenter Finland, and the U.S. Department of Health and Human Services National Institutes of Health grants MH085320 and AR053100 (T.G.B.). K.P. has been funded by the Finnish Cancer Institute. A.D.C. was supported by COSTAR Program NIDCR grant DE014318. ",

year = "2014",

doi = "10.1016/j.celrep.2014.03.047",

language = "English (US)",

volume = "7",

pages = "654--660",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

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.

N1 - Funding Information: We thank Dr. Mikael Björklund for critical review of the manuscript and Hertta Perikangas-Hentunen, Sini Miettinen, and Michael Parker for technical assistance. This work was supported by the Academy of Finland Center of Excellence in Cancer Genetics, Finnish Cancer Organizations, Sigrid Juselius Foundation, Biocenter Finland, and the U.S. Department of Health and Human Services National Institutes of Health grants MH085320 and AR053100 (T.G.B.). K.P. has been funded by the Finnish Cancer Institute. A.D.C. was supported by COSTAR Program NIDCR grant DE014318.

PY - 2014

Y1 - 2014

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84899923205&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899923205&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2014.03.047

DO - 10.1016/j.celrep.2014.03.047

M3 - Article

C2 - 24746821

AN - SCOPUS:84899923205

SN - 2211-1247

VL - 7

SP - 654

EP - 660

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this