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

G. Sebastiaan Winkler, Klaas W. Mulder, Vivian J. Bardwell, Eric Kalkhoven, H. Th Marc Timmers

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

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) α. Promoter recruitment assays indicate that CNOT1 contains an intrinsic ability to mediate transcriptional repression. Furthermore, CNOT1 can interact with the ligand-binding domain of ERα 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 ERα 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.

Original languageEnglish (US)
Pages (from-to)3089-3099
Number of pages11
JournalEMBO Journal
Volume25
Issue number13
DOIs
StatePublished - Jul 12 2006

Keywords

  • Ccr4-Not
  • Nuclear receptor
  • Oestrogen
  • Transcriptional repression

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