Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms

Kati Kämpjärvi, Nam Hee Kim, Salla Keskitalo, Alison D. Clark, Pernilla Von Nandelstadh, Mikko Turunen, Tuomas Heikkinen, Min Ju Park, Netta Mäkinen, Kati Kivinummi, Susanna Lintula, Kristina Hotakainen, Heli Nevanlinna, Peter Hokland, Tom Böhling, Ralf Bützow, Jan Böhm, Jukka Pekka Mecklin, Heikki Järvinen, Mika KontroTapio Visakorpi, Jussi Taipale, Markku Varjosalo, Thomas G Boyer, Pia Vahteristo

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15 Scopus citations

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. Prostate 76:22-31, 2016.

Original languageEnglish (US)
Pages (from-to)22-31
Number of pages10
JournalProstate
Volume76
Issue number1
DOIs
StatePublished - Jan 1 2016

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Keywords

  • CDK8
  • kinase activity
  • MED12
  • Mediator
  • prostate cancer
  • uterine leiomyoma

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

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. Prostate, 76(1), 22-31. https://doi.org/10.1002/pros.23092