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

Abstract

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