title: Human Ccr4-Not complex is a ligand-dependent repressor of nuclear receptor-mediated transcription.
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) 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.
authors.affiliation: Department of Physiological Chemistry, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: G Sebastiaan
authors.initials: GS
authors.lastname: Winkler
authors.forename: Klaas W
authors.initials: KW
authors.lastname: Mulder
authors.forename: Vivian J
authors.initials: VJ
authors.lastname: Bardwell
authors.forename: Eric
authors.initials: E
authors.lastname: Kalkhoven
authors.forename: H Th Marc
authors.initials: HT
authors.lastname: Timmers
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D047488:Retinoid X Receptors / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C079592:CDC39 protein, S cerevisiae; D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D021122:Protein Subunits; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D004958:Estradiol