The oestrogen receptor regulates NF kappa B 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 rece ptor (ER) and involve direct interactions between the ER and DNA response e lements, 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 tran sfected ER alpha was able to activate expression of beta-galactosidase unde r 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-depen dent manner in HeLa cells but not in HEK-293 cells. ER alpha/E-2 also induc ed 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 re sults suggest that the ERa is capable of regulating gene expression in a ce ll-specific manner. We further investigated the mechanisms by which the ER alpha regulates gene expression in these systems by co-expressing the ER al pha 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 t he capacity of the ER alpha to modulate NF kappa B reporter gene activity i n HeLa cells. Furthermore, the expression of SRC-1 alpha or RIP-140 does no t enable the ER alpha to repress NF kappa B or to potentiate an AP-1 respon se in HEK-293 cells. This suggests that factors other than SRC-1 alpha or R IP-140 are responsible for the cell-specific effects seen with ER alpha (C) 1998 Elsevier Science Ltd. All rights reserved.