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Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19.
J Biol Chem. 2018 03 30; 293(13):4870-4882.JB

Abstract

Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate cyclin C (CycC)-dependent kinase 8 (CDK8) in Mediator, implicating impaired Mediator-associated CDK8 activity in the molecular pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of MED12 mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, we find that within the Mediator kinase module, MED13 directly binds to the MED12 C terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC-CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation and reveal an additional step in the MED12-dependent activation process, one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that UF-linked mutations in MED12 disrupt composite Mediator-associated kinase activity and identify CDK8/19 as prospective therapeutic targets in UFs.

Authors+Show Affiliations

From the Departments of Molecular Medicine and.From the Departments of Molecular Medicine and.From the Departments of Molecular Medicine and.the 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.Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.the Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia 30912, and.the Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia 30912, and.the Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.the Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia 30912, and.Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.the 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.From the Departments of Molecular Medicine and boyer@uthscsa.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29440396

Citation

Park, Min Ju, et al. "Oncogenic Exon 2 Mutations in Mediator Subunit MED12 Disrupt Allosteric Activation of Cyclin C-CDK8/19." The Journal of Biological Chemistry, vol. 293, no. 13, 2018, pp. 4870-4882.
Park MJ, Shen H, Spaeth JM, et al. Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19. J Biol Chem. 2018;293(13):4870-4882.
Park, M. J., Shen, H., Spaeth, J. M., Tolvanen, J. H., Failor, C., Knudtson, J. F., McLaughlin, J., Halder, S. K., Yang, Q., Bulun, S. E., Al-Hendy, A., Schenken, R. S., Aaltonen, L. A., & Boyer, T. G. (2018). Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19. The Journal of Biological Chemistry, 293(13), 4870-4882. https://doi.org/10.1074/jbc.RA118.001725
Park MJ, et al. Oncogenic Exon 2 Mutations in Mediator Subunit MED12 Disrupt Allosteric Activation of Cyclin C-CDK8/19. J Biol Chem. 2018 03 30;293(13):4870-4882. PubMed PMID: 29440396.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19. AU - Park,Min Ju, AU - Shen,Hailian, AU - Spaeth,Jason M, AU - Tolvanen,Jaana H, AU - Failor,Courtney, AU - Knudtson,Jennifer F, AU - McLaughlin,Jessica, AU - Halder,Sunil K, AU - Yang,Qiwei, AU - Bulun,Serdar E, AU - Al-Hendy,Ayman, AU - Schenken,Robert S, AU - Aaltonen,Lauri A, AU - Boyer,Thomas G, Y1 - 2018/02/13/ PY - 2018/01/03/received PY - 2018/01/28/revised PY - 2018/2/15/pubmed PY - 2019/4/9/medline PY - 2018/2/15/entrez KW - CDK19 KW - CDK8 KW - MED12 KW - Mediator KW - RNA polymerase II KW - allosteric regulation KW - cancer KW - cyclin-dependent kinase (CDK) KW - gene transcription KW - transcription coregulator KW - tumor KW - uterine leiomyoma SP - 4870 EP - 4882 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 293 IS - 13 N2 - Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate cyclin C (CycC)-dependent kinase 8 (CDK8) in Mediator, implicating impaired Mediator-associated CDK8 activity in the molecular pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of MED12 mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, we find that within the Mediator kinase module, MED13 directly binds to the MED12 C terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC-CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation and reveal an additional step in the MED12-dependent activation process, one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that UF-linked mutations in MED12 disrupt composite Mediator-associated kinase activity and identify CDK8/19 as prospective therapeutic targets in UFs. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29440396/Oncogenic_exon_2_mutations_in_Mediator_subunit_MED12_disrupt_allosteric_activation_of_cyclin_C_CDK8/19_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=29440396 DB - PRIME DP - Unbound Medicine ER -