Elucidation of
kinase-initiated routes by which the
estrogen receptors alpha and beta (
ERalpha and
ERbeta) control gene transcription, along with evidence of distinct
biologic outcomes in response to
ligands that can selectively activate nongenotropic signaling of the ERs or the
androgen receptor, suggest that the ERs control a range of genes wider than that regulated by their direct association with
DNA. To ascertain the extent and significance of nongenotropic ER-mediated transcription, we employed transduced HeLa cells expressing wild-type
ERalpha or the
ligand binding domain of
ERalpha localized to the cell membrane (E-Mem), the OB-6 osteoblastic cell line, MCF-7
breast carcinoma cells and uteri from mice treated with 17beta-estradiol (E(2)), or the nongenotropic signaling activator
4-estren-3alpha,17beta-diol (
estren). E(2) and
estren induced ERK1/2 and Akt phosphorylation in
ERalpha or E-Mem stably transfected HeLa cells; however, the phosphorylation kinetics differed between the two cell lines. In all four models, nongenotropic ER actions regulated a population of genes distinct from those regulated by genotropic ER actions. Specifically, the expression of Wnt2, Frizzled10, Egr-1, and c-Fos was strongly up-regulated in E-Mem-containing HeLa cells treated with E(2) or
estren, or in
ERalpha-containing HeLa cells treated with
estren. Up-regulation of Frizzled10 by
estren was reproduced in MCF-7 cells. Egr-1 was up-regulated by both
estren and E(2); but
complement 3, only by E(2) in the uteri.
Estren had no effect on
complement 3,
cathepsin D,
progesterone receptor, bcl-2, and
cyclin D1 in MCF-7 cells, whereas E(2) up-regulated all these
estrogen response element or activating protein-1-containing genes. These results support an extensive divergence in gene expression depending on the mode of ER activation.