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Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms.
Prostate. 2016 Jan; 76(1):22-31.P

Abstract

BACKGROUND

Mediator is a multiprotein interface between eukaryotic gene-specific transcription factors and RNA polymerase II. Mutations in exon 2 of the gene encoding MED12, a key subunit of the regulatory kinase module in Mediator, are extremely frequent in uterine leiomyomas, breast fibroadenomas, and phyllodes tumors. These mutations disrupt kinase module interactions and lead to diminished Mediator-associated kinase activity. MED12 mutations in exon 26, resulting in a substitution of leucine 1224 to phenylalanine (L1224F), have been recurrently observed in prostate cancer.

METHODS

To elucidate the molecular mechanisms leading to tumorigenesis in prostate cancer, we analyzed global interaction profiles of wild-type and L1224F mutant MED12 with quantitative affinity purification-mass spectrometry (AP-MS). Immunoprecipitation and kinase activity assay were used to further assess the interactions between Mediator complex subunits and kinase activity. The presence of L1224F mutation was analyzed in altogether 877 samples representing prostate hyperplasia, prostate cancer, and various tumor types in which somatic MED12 mutations have previously been observed.

RESULTS

In contrast to N-terminal MED12 mutations observed in uterine leiomyomas, the L1224F mutation compromises neither the interaction of MED12 with kinase module subunits Cyclin C and CDK8/19 nor Mediator-associated CDK activity. Instead, the L1224F mutation was shown to affect interactions between MED12 and other Mediator components (MED1, MED13, MED13L, MED14, MED15, MED17, and MED24). Mutation screening revealed one mutation in a Finnish (Caucasian) prostate cancer patient, whereas no mutations in any other tumor type were observed.

CONCLUSIONS

Specific somatic MED12 mutations in prostate cancer and uterine leiomyomas accumulate in two separate regions of the gene and promote tumorigenesis through clearly distinct mechanisms.

Authors+Show Affiliations

Genome-Scale Biology Research Program and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.Institute of Biotechnology, University of Helsinki, Helsinki, Finland.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.Genome-Scale Biology Research Program and Department of Pathology, University of Helsinki, Helsinki, Finland.Genome-Scale Biology Research Program and Department of Pathology, University of Helsinki, Helsinki, Finland.Genome-Scale Biology Research Program and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.Genome-Scale Biology Research Program and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.Institute of Biosciences and Medical Technology - BioMediTech and Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, Finland.Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.Department of Pathology, The Laboratory of Helsinki University Central Hospital (HUSLAB), Helsinki University Central Hospital and Medicum, University of Helsinki, Helsinki, Finland.Department of Pathology, The Laboratory of Helsinki University Central Hospital (HUSLAB), Helsinki University Central Hospital and Medicum, University of Helsinki, Helsinki, Finland.Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland.Department of Surgery, Jyväskylä Central Hospital and University of Eastern Finland, Jyväskylä, Finland.Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.Hematology Research Unit Helsinki, Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.Institute of Biosciences and Medical Technology - BioMediTech and Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, Finland.Genome-Scale Biology Research Program and Department of Pathology, University of Helsinki, Helsinki, Finland.Institute of Biotechnology, University of Helsinki, Helsinki, Finland.Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.Genome-Scale Biology Research Program and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Pub Type(s)

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

Language

eng

PubMed ID

26383637

Citation

Kämpjärvi, Kati, et al. "Somatic MED12 Mutations in Prostate Cancer and Uterine Leiomyomas Promote Tumorigenesis Through Distinct Mechanisms." The Prostate, vol. 76, no. 1, 2016, pp. 22-31.
Kämpjärvi K, Kim NH, Keskitalo S, et al. Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms. Prostate. 2016;76(1):22-31.
Kämpjärvi, K., Kim, N. H., Keskitalo, S., Clark, A. D., von Nandelstadh, P., Turunen, M., Heikkinen, T., Park, M. J., Mäkinen, N., Kivinummi, K., Lintula, S., Hotakainen, K., Nevanlinna, H., Hokland, P., Böhling, T., Bützow, R., Böhm, J., Mecklin, J. P., Järvinen, H., ... Vahteristo, P. (2016). Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms. The Prostate, 76(1), 22-31. https://doi.org/10.1002/pros.23092
Kämpjärvi K, et al. Somatic MED12 Mutations in Prostate Cancer and Uterine Leiomyomas Promote Tumorigenesis Through Distinct Mechanisms. Prostate. 2016;76(1):22-31. PubMed PMID: 26383637.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms. AU - Kämpjärvi,Kati, AU - Kim,Nam Hee, AU - Keskitalo,Salla, AU - Clark,Alison D, AU - von Nandelstadh,Pernilla, AU - Turunen,Mikko, AU - Heikkinen,Tuomas, AU - Park,Min Ju, AU - Mäkinen,Netta, AU - Kivinummi,Kati, AU - Lintula,Susanna, AU - Hotakainen,Kristina, AU - Nevanlinna,Heli, AU - Hokland,Peter, AU - Böhling,Tom, AU - Bützow,Ralf, AU - Böhm,Jan, AU - Mecklin,Jukka-Pekka, AU - Järvinen,Heikki, AU - Kontro,Mika, AU - Visakorpi,Tapio, AU - Taipale,Jussi, AU - Varjosalo,Markku, AU - Boyer,Thomas G, AU - Vahteristo,Pia, Y1 - 2015/09/18/ PY - 2015/08/05/received PY - 2015/08/31/accepted PY - 2015/9/19/entrez PY - 2015/9/19/pubmed PY - 2016/5/26/medline KW - CDK8 KW - MED12 KW - Mediator KW - kinase activity KW - prostate cancer KW - uterine leiomyoma SP - 22 EP - 31 JF - The Prostate JO - Prostate VL - 76 IS - 1 N2 - BACKGROUND: Mediator is a multiprotein interface between eukaryotic gene-specific transcription factors and RNA polymerase II. Mutations in exon 2 of the gene encoding MED12, a key subunit of the regulatory kinase module in Mediator, are extremely frequent in uterine leiomyomas, breast fibroadenomas, and phyllodes tumors. These mutations disrupt kinase module interactions and lead to diminished Mediator-associated kinase activity. MED12 mutations in exon 26, resulting in a substitution of leucine 1224 to phenylalanine (L1224F), have been recurrently observed in prostate cancer. METHODS: To elucidate the molecular mechanisms leading to tumorigenesis in prostate cancer, we analyzed global interaction profiles of wild-type and L1224F mutant MED12 with quantitative affinity purification-mass spectrometry (AP-MS). Immunoprecipitation and kinase activity assay were used to further assess the interactions between Mediator complex subunits and kinase activity. The presence of L1224F mutation was analyzed in altogether 877 samples representing prostate hyperplasia, prostate cancer, and various tumor types in which somatic MED12 mutations have previously been observed. RESULTS: In contrast to N-terminal MED12 mutations observed in uterine leiomyomas, the L1224F mutation compromises neither the interaction of MED12 with kinase module subunits Cyclin C and CDK8/19 nor Mediator-associated CDK activity. Instead, the L1224F mutation was shown to affect interactions between MED12 and other Mediator components (MED1, MED13, MED13L, MED14, MED15, MED17, and MED24). Mutation screening revealed one mutation in a Finnish (Caucasian) prostate cancer patient, whereas no mutations in any other tumor type were observed. CONCLUSIONS: Specific somatic MED12 mutations in prostate cancer and uterine leiomyomas accumulate in two separate regions of the gene and promote tumorigenesis through clearly distinct mechanisms. SN - 1097-0045 UR - https://www.unboundmedicine.com/medline/citation/26383637/Somatic_MED12_mutations_in_prostate_cancer_and_uterine_leiomyomas_promote_tumorigenesis_through_distinct_mechanisms_ L2 - https://doi.org/10.1002/pros.23092 DB - PRIME DP - Unbound Medicine ER -