Estrogen Receptor (ER)-β Reduces ERα-Regulated Gene Transcription, Supporting a “Ying Yang” Relationship between ERα and ERβ in Mice
Tóm tắt
Estrogen is of importance for the regulation of adult bone metabolism. The aim of the present study was to determine the role of estrogen receptor-β (ERβ) in vivo on global estrogen-regulated transcriptional activity in bone. The effect of estrogen in bone of ovariectomized mice was determined using microarray analysis including 9400 genes. Most of the genes (95% = 240 genes) that were increased by estrogen in wild-type (WT) mice were also increased by estrogen in ERβ-inactivated mice. Interestingly, the average stimulatory effect of estrogen on the mRNA levels of these genes was 85% higher in ERβ-inactivated than in WT mice, demonstrating that ERβ reduces estrogen receptor-α (ERα)-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ERα-inactivated mice was intermediate between that seen in WT and ERαβ double-inactivated mice. Thus, ERβ inhibits ERα-mediated gene transcription in the presence of ERα, whereas, in the absence of ERα, it can partially replace ERα. In conclusion, our in vivo data indicate that an important physiological role of ERβ is to modulate ERα-mediated gene transcription supporting a “Ying Yang” relationship between ERα and ERβ in mice.
Từ khóa
Tài liệu tham khảo
Sims, 2000, In vivo analysis of male and female estrogen receptor α, β and double knockouts reveals a dual role for ERβ in bone remodelling., J Bone Miner Res, 15, 1088
Windahl, 1999, Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERβ(−/−) mice., J Clin Invest, 104, 895, 10.1172/JCI6730
Windahl, 2001, Female estrogen receptor β−/− mice are partially protected against age-related trabecular bone loss., J Bone Miner Res, 16, 1388, 10.1359/jbmr.2001.16.8.1388
Pettersson, 1997, Mouse estrogen receptor β forms estrogen response element-binding heterodimers with estrogen receptor α., Mol Endocrinol, 11, 1486
Pettersson, 2000, Estrogen receptor β acts as a dominant regulator of estrogen signaling., Oncogene, 19, 4970, 10.1038/sj.onc.1203828
Hall, 1999, The estrogen receptor β-isoform (ERβ) of the human estrogen receptor modulates ERα transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens., Endocrinology, 140, 5566, 10.1210/endo.140.12.7179
Paech, 1997, Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites., Science, 277, 1508, 10.1126/science.277.5331.1508
Weihua, 2000, Estrogen receptor (ER)β, a modulator of ERα in the uterus., Proc Natl Acad Sci USA, 97, 5936, 10.1073/pnas.97.11.5936
Weihua, 2001, A role for estrogen receptor β in the regulation of growth of the ventral prostate., Proc Natl Acad Sci USA, 98, 6330, 10.1073/pnas.111150898
Pendaries, 2002, The AF-1 activation-function of ERα may be dispensable to mediate the effect of estradiol on endothelial NO production in mice., Proc Natl Acad Sci USA, 99, 2205, 10.1073/pnas.042688499
Lindberg, 2002, Estrogen receptor specificity for the effects of estrogen in ovariectomized mice., J Endocrinol, 174, 167, 10.1677/joe.0.1740167
Nemere, 1998, Membrane receptors for steroid hormones: a case for specific cell surface binding sites for vitamin D metabolites and estrogens., Biochem Biophys Res Commun, 248, 443, 10.1006/bbrc.1998.8492
Le Mellay, 1999, Gα(q/11) and gβγ proteins and membrane signaling of calcitriol and estradiol., J Cell Biochem, 75, 138, 10.1002/(SICI)1097-4644(19991001)75:1<138::AID-JCB14>3.0.CO;2-I
Kousteni, 2001, Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity., Cell, 104, 719
Giangrande, 1997, Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor., J Biol Chem, 272, 32889, 10.1074/jbc.272.52.32889
Oakley, 1996, The human glucocorticoid receptor β isoform. Expression, biochemical properties, and putative function., J Biol Chem, 271, 9550, 10.1074/jbc.271.16.9550
Vegeto, 1993, Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function., Mol Endocrinol, 7, 1244
Omoto, 2001, Expression, function, and clinical implications of the estrogen receptor β in human lung cancers., Biochem Biophys Res Commun, 285, 340, 10.1006/bbrc.2001.5158
Lindberg, 2001, Estrogen receptor specificity in the regulation of the skeleton in female mice., J Endocrinol, 171, 229, 10.1677/joe.0.1710229
Krege, 1998, Generation and reproductive phenotypes of mice lacking estrogen receptor β., Proc Natl Acad Sci USA, 95, 15677, 10.1073/pnas.95.26.15677
Lubahn, 1993, Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene., Proc Natl Acad Sci USA, 90, 11162, 10.1073/pnas.90.23.11162
Vidal, 2000, Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice., Proc Natl Acad Sci USA, 97, 5474, 10.1073/pnas.97.10.5474