Estrogen targets genes involved in protein processing, calcium homeostasis, and Wnt signaling in the mouse uterus independent of estrogen receptor-alpha and -beta.
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.
Das
S K
SK
Department of Obstetrics & Gynecology, the Department of Molecular & Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. sdas@kumc.edu
Tan
J
J
Raja
S
S
Halder
J
J
Paria
B C
BC
Dey
S K
SK
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D011374:Progesterone / Q000494:pharmacology; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D011374:Progesterone; D002118:Calcium