The oestrogen receptor regulates NFκB and AP-1 activity in a cell-specific manner

Oestrogens regulate the expression of genes both positively and negatively in a range of cell types. These effects are mediated via the oestrogen receptor (ER) and involve direct interactions between the ER and DNA response elements, as well as interactions between the ER and other nuclear proteins. We have examined the potential of the ER alpha to regulate the expression of reporter genes under the control of oestrogen response elements (EREs), NF kappa B response elements (NREs) or AP-1/TPA response elements (TREs) in HeLa cells and in human embryonic kidney (HEK-293) cells. Transiently transfected ER alpha was able to activate expression of beta-galactosidase under the control df EREs in an oestradiol (E-2)-dependent manner in both HeLa and HEK-293 cells. The ER alpha was able to repress by 80% the TNF-mediated expression of beta-galactosidase under the control of NREs in an E-2-dependent manner in HeLa cells but not in HEK-293 cells. ER alpha/E-2 also induced a two-fold potentiation of TPA-mediated expression of beta-galactosidase under the control of TREs in HeLa cells but not in HEK-293 cells. These results suggest that the ERa is capable of regulating gene expression in a cell-specific manner. We further investigated the mechanisms by which the ER alpha regulates gene expression in these systems by co-expressing the ER alpha and the reporter gene constructs with known cofactors of the ER alpha. We have shown that expression of steroid receptor coactivator-1 alpha (SRC-1 alpha) and receptor interacting protein-140 (RIP-140) have no effect on the capacity of the ER alpha to modulate NF kappa B reporter gene activity in HeLa cells. Furthermore, the expression of SRC-1 alpha or RIP-140 does not enable the ER alpha to repress NF kappa B or to potentiate an AP-1 response in HEK-293 cells. This suggests that factors other than SRC-1 alpha or RIP-140 are responsible for the cell-specific effects seen with ER alpha (C) 1998 Elsevier Science Ltd. All rights reserved.