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Submitted on November 15, 2002
Accepted on May 29, 2003
1 Research Laboratories of Schering AG, Berlin, Germany
* To whom correspondence should be addressed. E-mail: bernard.haendler{at}schering.de.
Besides the steroid receptor elements (SREs) which are recognized by several steroid receptors, a second class of DNA elements exhibiting selectivity for the androgen receptor (AR) and named androgen response elements (AREs) has been identified. Here we provide evidence for the differential role of these element classes in modulating AR function. AR complexes attached to response elements representative of each class were purified. Limited protease digests of ARE- or SRE-bound AR complexes led to the generation of different patterns, in line with differential accessibilities. In transactivation assays, mutations in the AR dimerization interface of the DNA-binding domain had various effects, depending on the response elements tested. The R598D mutant displayed much enhanced activity on SREs whereas far less effect was seen on the selective AREs. The A596T mutant had reduced activity on AREs but not on SREs. Ectopic expression of the coactivators TIF2 and ARA55 stimulated AR activity to different extents, depending on the response element. When using CRISP-1 SRE as reference, the most significant difference was observed with Pem ARE-2. A differential response of each element class was furthermore observed in presence of two enzymes involved in the sumoylation pathway. Ubc9 overexpression enhanced AR action conveyed by SREs whereas little effect was seen on Pem ARE-1 and repression on Pem ARE-2. PIASx
overexpression had little influence on SRE-mediated AR activity but was repressive when using AREs. Altogether these results demonstrate that DNA response elements play an important modulatory role in transmitting AR action and may be determinative for specificity of gene expression in cell or tissue types.
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