Abstract
Estrogen actions in target organs are normally mediated via activation of nuclear estrogen receptors (ERs). By using mRNA differential display technique, we show, herein, that estradiol-17beta (E(2)) and its catechol metabolite 4-hydroxy-E(2) (4OHE(2)) can modulate uterine gene expression in ERalpha(-/-) mice. Whereas administration of E(2) or 4OHE(2) rapidly up-regulated (4-8-fold) the expression of immunoglobulin heavy chain binding protein (Bip), calpactin I (CalP), calmodulin (CalM), and Sik similar protein (Sik-SP) genes in ovariectomized wild-type or ERalpha(-/-) mice, the expression of secreted frizzled related protein-2 (SFRP-2) gene was down-regulated (4-fold). Bip, CalP, and CalM are calcium-binding proteins and implicated in calcium homeostasis, whereas SFRP-2 is a negative regulator of Wnt signaling. Bip and Sik-SP also possess chaperone-like functions. Administration of ICI-182,780 or cycloheximide failed to influence these estrogenic responses, demonstrating that these effects occur independent of ERalpha, ERbeta, or protein synthesis. In situ hybridization showed differential cell-specific expression of these genes in wild-type and ERalpha(-/-) uteri. Although progesterone can antagonize or synergize estrogen actions, it had minimal effects on these estrogenic responses. Collectively, the results demonstrate that estrogens have a unique ability to influence specific genes in the uterus not involving classical nuclear ERs.
Highlights
Estrogens regulate diverse physiological responses including normal functioning of the reproductive and cardiovascular systems and bone metabolism [1,2,3]
MRNA expression of four of the genes, glucose-regulated protein-78 kDa (GRP78)/immunoglobulin heavy chain binding protein (Bip), calpactin I (CalP), calmodulin (CalM), and SIK-similar protein (Sik-SP) was up-regulated, the expression of the secreted frizzled-related protein-2 (SFRP-2) was down-regulated in the uterus by E2 or 4OHE2 in both the wild-type and estrogen receptors (ERs)␣(Ϫ/Ϫ) mice. We observed that these estrogenic responses are not influenced by an ER antagonist ICI-182,780 (ICI), a protein synthesis inhibitor cycloheximide (Cyhx), or progesterone, suggesting that these effects occur independent of ER␣, ER, protein synthesis, or progesterone receptor (PR)
This response was not inhibited by prior administration of an ER antagonist, ICI, and was accompanied by early estrogenic responses, such as uterine water imbibition and macromolecular uptake [7]
Summary
Estrogens regulate diverse physiological responses including normal functioning of the reproductive and cardiovascular systems and bone metabolism [1,2,3]. A myriad of estrogenic effects occurs rapidly within seconds or minutes These responses do not require RNA or protein synthesis and are considered to be mediated by estrogen binding to the plasma membrane (10 –12). MRNA expression of four of the genes, glucose-regulated protein-78 kDa (GRP78)/immunoglobulin heavy chain binding protein (Bip), calpactin I (CalP), calmodulin (CalM), and SIK-similar protein (Sik-SP) was up-regulated, the expression of the secreted frizzled-related protein-2 (SFRP-2) was down-regulated in the uterus by E2 or 4OHE2 in both the wild-type and ER␣(Ϫ/Ϫ) mice. Our present results showing the influence of estrogen on uterine expression of genes that are involved in three fundamental cellular functions, such as protein processing, calcium homeostasis, and Wnt signaling independent of the classical ER or PR pathway, suggest diverse mode of estrogen actions
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