title: A role for cofactors in synergistic and cell-specific activation by retinoic acid receptors and retinoid X receptor.
abstract: Transcriptional activation is thought to be mediated by DNA-bound activators through interaction with a basal transcription factor thereby stabilizing the pre-initiation complex. For such interaction cofactors such as TAFs, bridging proteins, mediators or intermediary proteins are required by binding simultaneously to the activator and the target. We have investigated the activation functions (AFs) of both RARbeta and RXRalpha and show that both activators contain two homologous AFs. By comparing the capacity to activate transcription by these AFs on several promoters, both as full-length receptors and as fusion-proteins of AFs with the DNA-binding domain of the yeast transcription factor GAL-4, we were able to show that these AFs function by different mechanisms. We found that the activity of these AFs is cell-type specific, as they are more active in certain cell lines than in others. Furthermore we observed that the AFs of RARbeta and RXRalpha can activate transcription synergistically both as GAL-fusion protein and with full-length receptors. For AF-2 of RAR beta we observed cell type-dependent difference in synergistic activation and we show that the E1A protein, which functions as a cofactor for RAR beta, permits synergistic activation in cell lines in which in the absence of this cofactor transcription occurs non-synergistically. We propose a model in which several non cell type specific cofactors and cell-specific cofactors act together to form a more stable pre-initiation complex explaining the observed cell-specific synergistic activation.
authors.affiliation: Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, Netherlands.
authors.forename: G E
authors.initials: GE
authors.lastname: Folkers
authors.forename: B
authors.initials: B
authors.lastname: Van der Burg
authors.forename: P T
authors.initials: PT
authors.lastname: Van der Saag
mesh_terms: D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000473:pathology; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D007668:Kidney / Q000196:embryology; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin