The relative contribution exerted by AF-1 and AF-2 transactivation functions in estrogen receptor α transcriptional activity depends upon the differentiation stage of the cell

Abstract

The activity of the transactivation functions (activation function (AF)-1 and AF-2) of the estrogen receptor α (ERα) is cell-specific. This study aimed to decipher the yet unclear mechanisms involved in this differential cell sensitivity, with particular attention to the specific influence that cell differentiation may have on these processes. Hence, we comparatively evaluated the permissiveness of cells to either ERα AFs in two different cases: (i) a series of cell lines originating from a common tissue, but with distinct differentiation phenotypes; and (ii) cell lines that undergo differentiation processes in culture. These experiments demonstrate that the respective contribution that AF-1 and AF-2 make toward ERα activity varies in a cell differentiation stage-dependent manner. Specifically, whereas AF-1 is the dominant AF involved in ERα transcriptional activity in differentiated cells, the more a cell is de-differentiated the more this cell mediates ERα signaling through AF-2. For instance, AF-2 is the only active AF in cells that have achieved their epithelial-mesenchymal transition. Moreover, the stable expression of a functional ERα in strictly AF-2 permissive cells restores an AF-1-sensitive cell context. These results, together with data obtained in different ERα-positive cell lines tested strongly suggest that the transcriptional activity of ERα relies on its AF-1 in most estrogen target cell types.