Mutual cross-interference between glucocorticoid receptor and CREB inhibits transactivation in placental cells.

Transcription of the glycoprotein hormone alpha-subunit gene in placental cells is repressed by glucocorticoids, an effect that is mediated through the glucocorticoid receptor (GR). Although the DNA-binding domain of GR has been shown to be important, mutation of the previously identified GR-binding sites in the alpha-subunit promoter fails to abolish repression. Furthermore, mutant receptors in which the DNA-binding specificity is converted to ERE binding or in which the first zinc finger is substituted with that from thyroid receptor remain fully inhibitory, indicating that specific DNA binding to the alpha-subunit gene is not important for repression. Inhibition by GR is only effective when the alpha-subunit promoter is activated by CREB, implicating CREB as the target for GR-mediated repression. Reciprocally, overexpression of CREB interferes with GR-mediated transcriptional activation of MMTV. This activity is not affected by the phosphorylation state of CREB. Despite the mutual cross-interference with activation of gene expression, GR and CREB do not appear to have a high-affinity protein:protein interaction in vitro. Nonetheless, GR and CREB may interact directly in vivo possibly through a third protein or, more likely, may sequester a mutually required target protein.