Estrogen suppresses uterine epithelial apoptosis by inducing birc1 expression.
The decision whether or not a cell undergoes apoptosis is determined by the opposing forces of pro- and antiapoptotic effectors. Here we demonstrate genetically that estrogen can tip this balance toward cell survival in uterine epithelial cells by inducing the expression of baculoviral inhibitors of apoptosis repeat-containing 1 (Birc1), a family of antiapoptotic proteins. In neonatal mice, both 17beta-estradiol and the potent synthetic estrogen diethylstilbestrol strongly suppress uterine epithelial apoptosis while markedly elevating Birc1 transcript level in an estrogen receptor-alpha-dependent manner. The induction of Birc1 before any effect on apoptosis suppression and failure of diethylstilbestrol to completely inhibit apoptosis in Birc1a-deficient uterine epithelium indicate a functional role for Birc1a in estrogen-mediated apoptosis suppression. In ovariectomized adult mice, expression of Birc1 is also induced by ovarian hormones, suggesting a role for these proteins in normal uterine physiology. We propose that by binding to active caspases, Birc1 proteins can eliminate them through proteasome degradation. These results for the first time establish Birc1 proteins as functional targets of estrogen in suppressing apoptosis in the uterus.
Yin
Yan
Y
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Huang
Wei-Wei
WW
Lin
Congxing
C
Chen
Hong
H
MacKenzie
Alex
A
Ma
Liang
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism; D004054:Diethylstilbestrol / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014599:Uterus / Q000166:cytology
D047628:Estrogen Receptor alpha; D004967:Estrogens; C496801:Naip1 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D004958:Estradiol; D004054:Diethylstilbestrol; D051057:Proto-Oncogene Proteins c-akt; D053453:Caspase 9