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This version published online on December 29, 2005
Endocrinology, doi:10.1210/en.2005-1314
A more recent version of this article appeared on April 1, 2006
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Submitted on October 17, 2005
Accepted on December 19, 2005

Classical Genotropic versus Kinase-initiated Regulation of Gene Transcription by the Estrogen Receptor Alpha

M. Almeida, L. Han, C. A. O'Brien, S. Kousteni, and S. C. Manolagas*

Division of Endocrinology & Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR 72205

* To whom correspondence should be addressed. E-mail: manolagasstavros{at}uams.edu.

Elucidation of kinase-initiated routes by which the estrogen receptors {alpha} and {beta} (ER{alpha} and ER{beta}) control gene transcription, along with evidence of distinct biologic outcomes in response to ligands that can selectively activate nongenotropic signaling of the estrogen or androgen receptors, suggest that the ERs control a range of genes wider than that regulated by its direct association with DNA. To ascertain the extent and significance of nongenotropic ER-mediated transcription, we employed transduced HeLa cells expressing wild-type ER{alpha} or the ligand binding domain of ER{alpha} localized to the cell membrane (E-Mem), the OB-6 osteoblastic cell line, MCF-7 breast carcinoma cells and uteri from mice treated with 17{beta}-estradiol or the nongenotropic signaling activator 4-estren-3{alpha},17{beta}-diol (estren). E2 and estren induced ERK1/2 and Akt phosphorylation in ER{alpha} or E-Mem stably transfected HeLa cells; however, the phosphorylation kinetics differed between the two cell lines. In all 4 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 E2 or estren, or in ER{alpha}-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 E2; but complement 3 (C3), only by E2 in the uteri. Estren had no effect on C3, cathepsin D, progesterone receptor, bcl-2 and cyclin D1 in MCF-7 cells, whereas E2 up-regulated all these ERE or AP-1-containing genes. These results support an extensive divergence in gene expression depending on the mode of ER activation.
Key words: estrogen receptor • kinases • transcription • bone • reproductive tissues




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