Abstract
Expression of retinoic acid receptor beta (RARbeta) is spatially and temporally restricted during embryonal development. Also during retinoic acid (RA)-dependent embryonal carcinoma (EC) cell differentiation, RARbeta expression is initially up-regulated, while in later phases of differentiation expression is down-regulated, by an unknown mechanism. To gain insight into the regulation of RARbeta, we studied the activity of the RARbeta2 promoter and mutants thereof in various cell lines. While the RARbeta2 promoter is activated by RA in a limited number of cell lines, synthetic RA-responsive reporters are activated in most cell types. We show that the expression levels of proteins that bind to the beta-retinoic acid response element (RAR/retinoid X receptors and orphan receptors) and also the differential expression of a number of coactivators modulate the RA response on both natural and synthetic reporters. We further show that cell type-specific activation of the RARbeta2 promoter is dependent on the promoter architecture including the spacing between retinoic acid response element and TATA-box and initiator sequence (betaINR). Mutation within these regions caused a decrease in the activity of this promoter in responsive EC cells, while an increase in activity in non-EC cell lines was observed. Cell-specific complexes were formed on the betaINR, suggesting that the betaINR contributes to cell-specific activation of the promoter. On this basis we propose that promoter context-dependent and more general RA response-determining mechanisms contribute to cell-specific RA-dependent activation of transcription.
Highlights
IntroductionCell-specific Activation of the retinoic acid receptor  (RAR)2 Promoter of the TATA-box [17, 18]
§ To whom correspondence should be addressed: Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
Cell-specific Activation of the retinoic acid receptor  (RAR)2 Promoter—Previously, we have reported that undifferentiated embryonal carcinoma (EC) cells express retinoic acid receptors (RARs) upon Retinoic acid (RA) treatment, whereas differentiated EC-cell derivatives do not [29]
Summary
Cell-specific Activation of the RAR2 Promoter of the TATA-box [17, 18] This retinoic acid response element was shown to be required for accurate expression in vitro [19] and in vivo (20 –22). Sequences upstream from this element functioning as a cyclic AMP-response element as well as putative thyroid hormone response element (TRE)-like sequences have been found that contribute to RA-dependent activation of this promoter [23]. In vivo footprint experiments have identified an INR element that is occupied in a RA-dependent manner in EC cells and contributes to RAR2 promoter activity [24]
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