Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling.
Estradiol-17beta (E(2)) causes cell proliferation in the uterine epithelium of mice and humans by signaling through its transcription factor receptor alpha (ERalpha). In this work we show that this signaling is mediated by the insulin-like growth factor 1 receptor (IGF1R) expressed in the epithelium, whose activation leads to the stimulation of the phosphoinositide 3-kinase/protein kinase B pathway leading to cyclin D1 nuclear accumulation and engagement with the canonical cell cycle machinery. This cyclin D1 nuclear accumulation results from the inhibition of glycogen synthase kinase 3beta (GSK3beta) activity caused by an inhibitory phosphorylation by protein kinase B. Once the IGF1 pathway is activated, inhibition of ER signaling demonstrates that it is independent of ER. Inhibition of GSK3beta in the absence of E(2) is sufficient to induce uterine epithelial cell proliferation, and GSK3beta is epistatic to IGF1 signaling, indicating a linear pathway from E(2) to cyclin D1. Exposure to E(2) is the major risk factor for endometrial cancer, suggesting that downstream activation of this IGF1-mediated pathway by mutation could be causal in the progression to ER-independent tumors.
Zhu
Liyin
L
Department of Developmental and Molecular Biology, Center of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Pollard
Jeffrey W
JW
D000818:Animals; D002455:Cell Division; D002467:Cell Nucleus / Q000502:physiology; D019938:Cyclin D1 / Q000502:physiology; D004261:DNA Replication; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D011960:Receptors, Estrogen / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014594:Uterine Neoplasms / Q000503:physiopathology; D014599:Uterus / Q000166:cytology* / Q000187:drug effects
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D019938:Cyclin D1; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3