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The promoter context is a decisive factor in establishing selective responsiveness to nuclear class II receptors

The vigorous retinoic acid (RA)‐dependent activation of the retinoic acid receptor β2 (RARβ2) gene in embryonal carcinoma (EC) cells is mediated by retinoid receptor heterodimers (RXR–RAR) binding to RAREs that are closely positioned to the TATA box and an EC cell‐specific co‐factor activity termed E1A‐LA. Using a series of direct repeat (DR) elements, we now show that positioning RXR–RAR in close proximity to the basal transcription machinery assembled on the TATA box is decisive in RA responsiveness in EC cells. Notably, a DR1 element functions predominantly as an RAR‐responsive element when placed in the context of the RARβ2 promoter. Moreover, DR3 and DR4 elements which mediate vitamin D3 and thyroid hormone responses, respectively, in other contexts, are converted to exclusive RAR response elements when placed in the RARβ2 promoter and EC cell context. In differentiated cells, the adenovirus E1A(13S) protein is required to achieve high level RA activation through all of the different DR elements placed in the RARβ2 context, suggesting that the molecular bridging function of E1A‐LA [E1A(13S)] is essential to redefining response element specificity. Finally, we show that the arrangement of cis‐acting elements as present in the RARβ2 promoter is not crucial, but rather the close positioning of the RAREs to the TATA. We conclude that the identity of a given cis‐acting element is defined not only by its affinity for the transactivator, but also by the context in which it is placed, as well as the cell type in which the transactivator is expressed.