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Browsing by Author "Chambon, P"
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Item Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element.(National Academy of Sciences, 1991-11-15) Leroy, P; Nakshatri, H; Chambon, PWe have characterized the promoter of the mouse retinoic acid receptor alpha 2 (mRAR-alpha 2) isoform. This promoter contains a retinoic acid response element (RARE) that closely resembles the RARE that is present in the RAR-beta 2 promoter. Moreover, RAR-alpha 2 and RAR-beta 2 proximal promoter sequences are similar to each other and generate transcripts whose respective start sites are located at similar positions. The RAR-alpha 2 RARE consists of two directly repeated 5'-GTTCA-3' motifs to which all three RARs (alpha, beta, and gamma) bind in vitro.Item RARs and RXRs: evidence for two autonomous transactivation functions (AF-1 and AF-2) and heterodimerization in vivo.(EMBO Press, 1993-06) Nagpal, S; Friant, S; Nakshatri, H; Chambon, PWe have previously reported that the AB regions of retinoic acid receptors (RARs and RXRs) contain a transcriptional activation function capable of modulating the activity of the ligand-dependent activation function present in the C-terminal DE regions of these receptors. However, we could not demonstrate that these AB regions possess an autonomous activation function similar to the AF-1s found in the AB regions of steroid hormone receptors. Using the mouse CRBPII promoter as a reporter gene, we now report that the AB regions of RAR alpha, beta and gamma, as well as those of RXR alpha and gamma, contain an autonomous, ligand-independent activation function, AF-1, which can efficiently synergize with AF-2s. Moreover, AF-1s account for the ligand-independent, constitutive activation of transcription by RXR alpha and gamma. We also show that RARs and RXRs preferentially heterodimerize in solution in cultured cells in vivo, through the dimerization interface present in their E region, irrespective of the presence of all-trans or 9-cis retinoic acid. Furthermore, our results indicate that homodimeric interactions are not observed in cultured cells in vivo under conditions where heterodimeric interactions readily occur, which is in agreement with previous observations showing the preferential binding of RAR-RXR heterodimers to RA response elements in vitro.Item A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter.(EMBO Press, 1991-08) Smith, W C; Nakshatri, H; Leroy, P; Rees, J; Chambon, PGenomic and cDNA sequences for the mouse cellular retinol binding protein I (mCRBPI) are presented. A specific cis-acting element responsible for retinoic acid (RA) inducibility of the mCRBPI promoter was identified and characterized. Deletion mapping of a CRBPI promoter--chloramphenicol acetyltransferase reporter gene construct localized this element to a 259 bp restriction fragment located approximately 1 kb upstream from the transcription start-site. A sequence closely resembling the previously characterized RA response element (RARE) of the RA receptor beta 2 (RAR-beta 2) promoter, and consisting of a direct repeat of the motif 5'-GGTCA-3' separated by three nucleotides, was found within this restriction fragment. Mutation of these 5'-GGTCA-3' motifs to GGAGC and GGGGC abolished RA-inducible transcription whereas a mutation to a direct repeat of the GTTCA motif found in the RARE of the RAR-beta 2 promoter resulted in enhanced inducibility. Oligonucleotides containing the direct repeat of the GGTCA motif were able to confer RA-dependent transcriptional enhancement to the herpes simplex thymidine kinase promoter, as well as to bind directly all three retinoic acid receptors (RARs) alpha, beta and gamma, as determined by gel retardation/shift assays. The control of CRBPI gene transcription by RA-RAR complexes interacting with the RARE characterized here may correspond to a feedback mechanism important in regulating retinoid metabolism and action.