GLUCOCORTICOID RECEPTOR TRANSCRIPTIONAL ACTIVITY DETERMINED BY SPACING OF RECEPTOR AND NONRECEPTOR DNA SITES

The glucocorticoid receptor (GR) displays distinct modes of regulation when bound at glucocorticoid response elements (GREs) bearing differe nt binding sequences and arrangements of binding sites. For example, i t has been shown to activate transcription synergistically with itself or with other regulatory factors, such as AP1, when bound to a consen sus palindromic element or ''simple GRE'' that is multimerized or link ed tightly with an API site. In contrast, at certain ''composite GREs' ' GR and AP1 bind to nonconsensus sequences, and GR either activates o r represses depending on the subunit composition of AP1, To uncouple t he contributions to regulatory behavior of binding sequences and bindi ng element arrangements, we examined GR action at ''paired elements,'' combinations of a simple GRE and a consensus AP1 site, separated by d ifferent distances. We found that GR synergized with either c-Jun or c -Jun-c-Fos at paired elements with GRE-AP1 site separations of greater than or equal to 26 base pairs. In contrast, paired elements with sep arations of 14-18 base pairs mimicked the composite GRE, i.e, GR syner gized with c-Jun and repressed c-Jun-c-Fos, In DNA binding studies, GR and AP1 cooccupied the paired elements, We conclude that the arrangem ent of binding sites within a compound response element can be a major determinant of regulatory factor action.