The oestrogen receptor regulates NFkappaB 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 ERalpha to regulate the expression of reporter genes under the control of oestrogen response elements (EREs), NFkappaB response elements (NREs) or AP-1/TPA response elements (TREs) in HeLa cells and in human embryonic kidney (HEK-293) cells. Transiently transfected ERalpha was able to activate expression of beta-galactosidase under the control of EREs in an oestradiol (E2)-dependent manner in both HeLa and HEK-293 cells. The ERalpha was able to repress by 80% the TNF-mediated expression of beta-galactosidase under the control of NREs in an E2-dependent manner in HeLa cells but not in HEK-293 cells. ERalpha/E2 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 ERalpha is capable of regulating gene expression in a cell-specific manner. We further investigated the mechanisms by which the ERalpha regulates gene expression in these systems by co-expressing the ERalpha and the reporter gene constructs with known cofactors of the ERalpha. We have shown that expression of steroid receptor coactivator-1 alpha (SRC-1alpha) and receptor interacting protein-140 (RIP-140) have no effect on the capacity of the ERalpha to modulate NFkappaB reporter gene activity in HeLa cells. Furthermore, the expression of SRC-1alpha or RIP-140 does not enable the ERalpha to repress NFkappaB or to potentiate an AP-1 response in HEK-293 cells. This suggests that factors other than SRC-1alpha or RIP-140 are responsible for the cell-specific effects seen with ERalpha.