BMP7/ActRIIB regulates estrogen-dependent apoptosis: new biomarkers for environmental estrogens.
A ligand-receptor pair, bone morphogenetic protein-7 (BMP7) and activin receptor IIB (actRIIB), was identified from a pool of DNA fragments recovered from MCF7 cells treated with 17beta-estradiol (E2) by chromatin immunoprecipitation with antiestrogen receptor-alphaantibody. The E2 responsiveness of both genes was confirmed in MCF cells and in the mouse uterus. Repeated treatment with E2 resulted in decreased expression of both actRIIB and BMP7 mRNA in the uteri of ovariectomized mice. A single oral administration of bisphenol A (BPA), an environmental estrogen, inhibited actRIIB and BMP7 expression and apoptosis in the luminal epithelium of the mouse uterus at diestrus (or early proestrus). This decrease, due to BPA administration, was restored by an estrogen receptor (ER) antagonist suggesting that it is mediated through ERs. These results suggest that E2 and BPA suppress estrogen-dependent apoptosis of epithelial cells of the endometrium through down-regulation of actRIIB and BMP7. Thus, we propose that BMP7 and actRIIB, a ligand-receptor pair, are involved in regulation of the apoptotic signaling pathway and might therefore be new biomarkers of the effects of environmental estrogens on the female reproductive tract.
Endocrine Disruptors and Dioxin Research Project, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan.
Takahiro
T
Kusumegi
Junko
J
Tanaka
Michihiro
M
Kawano
Junzo
J
Yonemoto
Chiharu
C
Tohyama
Hideko
H
Sone
D030301:Activin Receptors, Type II / Q000235:genetics*; D000395:Air Pollutants, Occupational / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D045744:Cell Line, Tumor; D002843:Chromatin / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D015386:Hazardous Substances / Q000633:toxicity; D006801:Humans; D051379:Mice; D010052:Ovariectomy; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger; D011960:Receptors, Estrogen / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014599:Uterus / Q000166:cytology / Q000276:immunology
D000395:Air Pollutants, Occupational; C525819:BMP7 protein, human; D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002843:Chromatin; D004967:Estrogens; D015386:Hazardous Substances; D011506:Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B