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  • The EMBO Journal (2006) 25, 3089 - 3099
  • doi:10.1038/sj.emboj.7601194

Published online: 15 June 2006

Human Ccr4-Not complex is a ligand-dependent repressor of nuclear receptor-mediated transcription

G Sebastiaan Winkler1, Klaas W Mulder1, Vivian J Bardwell2, Eric Kalkhoven3 and H Th Marc Timmers1

  1. Department of Physiological Chemistry, University Medical Centre Utrecht, Utrecht, The Netherlands
  2. Department of Genetics, Cell Biology and Development & Cancer Center, University of Minnesota, Minneapolis, MN, USA
  3. Department of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands

Correspondence to:

H Th Marc Timmers, Department of Physiological Chemistry, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Tel.: +31 30 253 8981; Fax: +31 30 253 9035; E-mail: h.t.m.timmers@med.uu.nl

Received 29 December 2005; Accepted 17 May 2006

The Ccr4-Not complex is a highly conserved regulator of mRNA metabolism. The transcription regulatory function of this complex in higher eukaryotes, however, is largely unexplored. Here we report that CNOT1, the large human subunit, represses the ligand-dependent transcriptional activation function of oestrogen receptor (ER) alpha. Promoter recruitment assays indicate that CNOT1 contains an intrinsic ability to mediate transcriptional repression. Furthermore, CNOT1 can interact with the ligand-binding domain of ERalpha in a hormone-dependent fashion and is recruited with other Ccr4-Not subunits to endogenous oestrogen-regulated promoters dependent on the presence of ligand. In addition, siRNA-mediated depletion of endogenous CNOT1 or other Ccr4-Not subunits in breast cancer cells results in deregulation of ERalpha target genes. Finally, CNOT1 interacts in a ligand-dependent manner with RXR and represses transcription mediated by several RXR heterodimers. These findings define a function for the human Ccr4-Not complex as a transcriptional repressor of nuclear receptor signalling that is relevant for the understanding of molecular pathways involved in cancer.

  • Keywords:

    • Ccr4-Not,
    • nuclear receptor,
    • oestrogen,
    • transcriptional repression