Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation (original) (raw)
- Article
- Published: 09 December 2007
- Na Yin1,
- Melanie Wissmann1,
- Natalia Kunowska1,
- Kristin Fischer1,
- Nicolaus Friedrichs2,
- Debasis Patnaik3,
- Jonathan M. G. Higgins3,
- Noelle Potier4,
- Karl-Heinz Scheidtmann5,
- Reinhard Buettner2 &
- …
- Roland Schüle1
Nature Cell Biology volume 10, pages 53–60 (2008)Cite this article
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An Erratum to this article was published on 01 February 2008
Abstract
Posttranslational modifications of histones such as methylation, acetylation and phosphorylation regulate chromatin structure and gene expression. Here we show that protein-kinase-C-related kinase 1 (PRK1) phosphorylates histone H3 at threonine 11 (H3T11) upon ligand-dependent recruitment to androgen receptor target genes. PRK1 is pivotal to androgen receptor function because PRK1 knockdown or inhibition impedes androgen receptor-dependent transcription. Blocking PRK1 function abrogates androgen-induced H3T11 phosphorylation and inhibits androgen-induced demethylation of histone H3. Moreover, serine-5-phosphorylated RNA polymerase II is no longer observed at androgen receptor target promoters. Phosphorylation of H3T11 by PRK1 accelerates demethylation by the Jumonji C (JmjC)-domain-containing protein JMJD2C. Thus, phosphorylation of H3T11 by PRK1 establishes a novel chromatin mark for gene activation, identifying PRK1 as a gatekeeper of androgen receptor-dependent transcription. Importantly, levels of PRK1 and phosphorylated H3T11 correlate with Gleason scores of prostate carcinomas. Finally, inhibition of PRK1 blocks proliferation of androgen receptor-induced tumour cell proliferation, making PRK1 a promising therapeutic target.
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Acknowledgements
We thank C. Beisenherz-Huss, C. Schächtele (ProQinase GmbH, Freiburg) and R. Schneider for providing reagents. We are obliged to T. Günther, H. Greschik, J. M. Müller and S. Naumovitz for discussions. We thank F. Klott for technical assistance. This work was supported by grants from the National Institutes of Health to J.M.G.H., the Deutsche Forschungsgemeinschaft, the Dr Hans Messner Stiftung and Deutsche Krebshilfe to R.S.
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Authors and Affiliations
- Universitäts-Frauenklinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, Freiburg, 79106, Germany
Eric Metzger, Na Yin, Melanie Wissmann, Natalia Kunowska, Kristin Fischer & Roland Schüle - Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, Bonn, 53127, Germany
Nicolaus Friedrichs & Reinhard Buettner - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA
Debasis Patnaik & Jonathan M. G. Higgins - Institut de Chimie LC3 – CNRS - UMR 7177, ISIS, 8 allée Gaspard Monge, Strasbourg, 67083, France
Noelle Potier - Institut für Genetik, Universität Bonn, Römerstrasse 16, Bonn, 53117, Germany
Karl-Heinz Scheidtmann
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Metzger, E., Yin, N., Wissmann, M. et al. Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation.Nat Cell Biol 10, 53–60 (2008). https://doi.org/10.1038/ncb1668
- Received: 03 October 2007
- Accepted: 23 November 2007
- Published: 09 December 2007
- Issue Date: January 2008
- DOI: https://doi.org/10.1038/ncb1668