title: Cell-specific inhibition of retinoic acid receptor-alpha silencing by the AF2/tau c activation domain can be overcome by the corepressor SMRT, but not by N-CoR.
abstract: The human retinoic acid receptor alpha (hRAR alpha) exhibits cell-specific transcriptional activity. Previously, it was shown that in the absence of hormone the wild-type receptor is a transcriptional silencer in L cells, whereas it lacks silencing function and is a weak activator in CV1 cells. Addition of hormone leads to a further increase in transactivation in CV1 cells. Thus, the retinoic acid response mediated by RAR alpha is weak in these cells. It was shown that the CV1-specific effect is due to the receptor C terminus. We show, that the failure of silencing by RAR is not due to a general lack of corepressors in CV1 cells, since the silencing domain of RAR is functionally active and exhibits active repression in these cells. Furthermore, we show that the conserved AF2/tau c activation function of RAR is responsible for the cell-specific inhibition of silencing. Thereby, the CV1 cell specificity was abolished by replacing AF2/tau c of RAR with the corresponding sequence of the thyroid hormone receptor. Thus, we find a new role of the C-terminal conserved activation function AF2/tau c in that, specifically, the RAR AF2/tau c-sequence is able to prevent silencing of RAR in a cell-specific manner. In addition, we show that the inhibitory effect of AF2/tau c in CV1 cells can be overcome by expression of the corepressor SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), but not by that of N-CoR (nuclear receptor corepressor). The expression of these two corepressors, however, had no measurable effect on RAR-mediated silencing in L cells. Thus, the expression of a corepressor can lead to a dramatic increase of hormonal response in a cell-specific manner.
authors.affiliation: Genetisches Institut der Justus-Liebig Universität, Giessen, Germany. Aria.Baniahmad@Gen.Bio.Uni-Giessen.de
authors.forename: A
authors.initials: A
authors.lastname: Baniahmad
authors.forename: U
authors.initials: U
authors.lastname: Dressel
authors.forename: R
authors.initials: R
authors.lastname: Renkawitz
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D007739:L Cells; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D015533:Transcriptional Activation; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; C539128:Ncor1 protein, mouse; C539131:Ncor2 protein, mouse; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin