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A central domain of cyclin D1 mediates nuclear receptor corepressor activity

Oncogene volume 24, pages 431–444 (2005)Cite this article

Abstract

Regulation of nuclear receptor activity is the focus of numerous ongoing studies to develop novel therapies for the treatment of hormone-related cancer. Although cyclin D1 functions to control the activity of several nuclear receptors, the region(s) of the protein responsible for such transcriptional comodulation remain poorly defined. Herein, we map the region of cyclin D1 required for binding and repression of the androgen receptor (AR) to a central, exclusively α-helical domain. Deletion of this domain disrupted AR binding and corepressor activity. Further investigations showed that this domain is sufficient for AR interaction and possesses the ability to bind histone deacetylase 3. Strikingly, overexpression of this repressor region attenuates cell cycle progression in prostatic adenocarcinoma cells. The requirement of this domain for nuclear receptor repression was conserved with respect to thyroid hormone receptor beta-1, whereas cyclin D1 activation of the estrogen receptor occurred independently of the central region. Together, these data identify a minimal repression module within cyclin D1 and demonstrate that the coactivator and corepressor functions of cyclin D1 are distinct. In addition, our data suggest that properties of the cyclin D1 central domain could be exploited to develop novel prostate cancer therapeutics.

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Acknowledgements

We thank Dr G Babcock and S Schwemberger for aid in acquiring flow cytometry data. We thank Dr E Knudsen and the Knudsen Laboratories for their technical assistance and critical reading of the manuscript. This work was supported by RO1 CA099996 and the Center for Environmental Genetics (Center Grant NIH/NIEHS P30-ES06096) (to KEK), NIH CA93237 (to JAD), the University of Cincinnati Distinguished Graduate Fellowship (to CEP and CJB), the Albert J Ryan Foundation (to CEP and CJB), and NIH training Grant #HDO7200-15 (CJB).

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Authors and Affiliations

  1. Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0521, USA

    Christin E Petre-Draviam, Erin B Williams, Craig J Burd, Hamed Moghadam & Karen E Knudsen

  2. Center for Environmental Genetics, Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0521, USA

    Andrew Gladden & J Alan Diehl

  3. Department of Biomedical Engineering, Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0521, USA

    Jaroslaw Meller

  4. Abramson Family Cancer Research Center, University of Pennsylvania Cancer Center, Philadelphia, PA, 19104, USA

    Karen E Knudsen

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  1. Christin E Petre-Draviam
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Correspondence to Karen E Knudsen.

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Petre-Draviam, C., Williams, E., Burd, C. et al. A central domain of cyclin D1 mediates nuclear receptor corepressor activity. Oncogene 24, 431–444 (2005). https://doi.org/10.1038/sj.onc.1208200

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