TRANSCRIPTIONAL CROSS-TALK, THE 2ND MODE OF STEROID-HORMONE RECEPTOR ACTION

Physiological and therapeutic activities of glucocorticoids and other steroid hormones are mediated by the family of steroid hormone recepto rs. In addition to the classical mode of receptor action which involve s binding as a dimer to regulatory sequences in target gene promoters and subsequent activation of transcription, a second mode of action is based predominantly on protein-protein interactions. As the paradigm of this so-called transcriptional cross-talk, the glucocorticoid recep tor (GR) and the AP-1 transcription factor interact on target gene pro moters which contain only a binding site for either one of the two tra nscription factors. Most frequently negative interference of both fact ors with each other's activity has been observed, for example, when AP -1 is composed of c-Fos and c-Jun; however, synergism is also possible under cell-specific conditions and when AP-1 is a homodimer of c-Jun. Since the detection of the GR/AP-1 cross-talk numerous other examples of transcription factor interactions have been described. Many member s of the nuclear hormone receptor superfamily, including class II rece ptors, have been shown to participate in such cross-talk. Moreover, th e transcription factor families of NF-kappa B/Rel as well as Stat, Oct , and C/EBP are engaged in cross-talk with steroid receptors. Despite the identification of a multitude of target genes which appear to be r egulated by this type of transcription factor interaction, the exact m olecular mechanism of the cross-talk has not yet been elucidated. This review discusses the current models to explain the molecular events o f transcription factor cross-talk. Concepts are emphasized which sugge st that the classical and the cross-talk mode of steroid receptor acti on can be triggered separately by the choice of specific ligands. A fi nal section summarizes the partially contradictory data which assign a certain type of receptor action to a biological response particularly in the immune system.